List of phenyltropanes explained

Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function. These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's and Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.^[1]) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article) Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

2-Carboxymethyl esters (phenyl-methylecgonines)

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.^[2]

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact. The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.

Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes (values)
monohalogen halide-phenyltropanes (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z)! Structure ! Short Name
i.e. Trivial IUPAC
(non-systematic) Name
(Singh's #)! R (para-substitution)
of benzene! DA
[³H]WIN 35428
IC₅₀ nM
(K_i nM)! 5HT
[³H]paroxetine
IC₅₀ nM
(K_i nM)! NE
[³H]nisoxetine
IC₅₀ nM
(K_i nM)! selectivity
5-HTT/DAT! selectivity
NET/DAT

	cocaine (benzoyloxytropane)	H	102 ± 12 241 ± 18^ɑ	1045 ± 89 112 ± 2^b	3298 ± 293 160 ± 15^c	10.2 0.5^d	32.3 0.7^e
	(para-hydrogen)phenyltropane WIN 35,065-2 (β-CPT) Troparil 11a	H	23 ± 5.0 49.8 ± 2.2^ɑ	1962 ± 61 173 ± 13^b	920 ± 73 37.2 ± 5.2^c	85.3 3.5^d	40.0 0.7^e
	para-fluorophenyltropane WIN 35,428 (β-CFT) 11b		14 (15.7 ± 1.4) 22.9 ± 0.4^ɑ	156 (810 ± 59) 100 ± 13^b	85 (835 ± 45) 38.6 ± 9.9^c	51.6 4.4^d	53.2 1.7^e
	para-nitrophenyltropane 11k	NO2	10.1 ± 0.10	?	?	?	?
	para-aminophenyltropane RTI-29^[3] 11j	NH2	9.8 24.8 ± 1.3^g	5110	151	521.4	15.4
	para-chlorophenyltropane RTI-31 11c		1.12 ± 0.06 3.68 ± 0.09^ɑ	44.5 ± 1.3 5.00 ± 0.05^b	37 ± 2.1 5.86 ± 0.67^c	39.7 1.3^d	33.0 1.7^e
	para-methylphenyltropane RTI-32 Tolpane 11f		1.71 ± 0.30 7.02 ± 0.30^ɑ	240 ± 27 19.38 ± 0.65^b	60 ± 0.53^e 8.42 ± 1.53^c	140 2.8^d	35.1 1.2^e
	para-bromophenyltropane RTI-51 Bromopane 11d		1.81 (1.69) ± 0.30	10.6 ± 0.24	37.4 ± 5.2	5.8	20.7
	para-iodophenyltropane RTI-55 (β-CIT) Iometopane 11e	I	1.26 ± 0.04 1.96 ± 0.09^ɑ	4.21 ± 0.3 1.74 ± 0.23^b	36 ± 2.7 7.51 ± 0.82^c	3.3 0.9^d	28.6 3.8^e
	para-hydroxyphenyltropane 11h	OH	12.1 ± 0.86	—	—	—	—
	para-methoxyphenyltropane 11i	OCH3	8.14 ± 1.3	—	—	—	—
	para-azidophenyltropane 11l	N3	2.12 ± 0.13	—	—	—	—
	para-trifluoromethylphenyltropane 11m	CF3	13.1 ± 2.2	—	—	—	—
	para-acetylaminophenyltropane 11n	NHCOCH3	64.2 ± 2.6	—	—	—	—
	para-propionylaminophenyltropane 11o	NHCOC2H5	121 ± 2.7	—	—	—	—
	para-ethoxycarbonylaminophenyltropane 11p	NHCO2C3H5	316 ± 48	—	—	—	—
	para-trimethylstannylphenyltropane 11q	Sn(CH3)3	144 ± 37	—	—	—	—
	para-ethylphenyltropane RTI-83 11g	Et	55 ± 2.1	28.4 ± 3.8 (2.58 ± 3.5)	4030 (3910) ± 381 (2360 ± 230)	0.5	73.3
	para-n-propylphenyltropane RTI-282^i 11r	n-C3H7	68.5 ± 7.1	70.4 ± 4.1	3920 ± 130	1.0	57.2
	para-isopropylphenyltropane 11s	CH(CH3)2	597 ± 52	191 ± 9.5	75000 ± 5820	0.3	126
	para-vinylphenyltropane RTI-359 11t	CH-CH2	1.24 ± 0.2	9.5 ± 0.8	78 ± 4.1	7.7	62.9
	para-methylethenylphenyltropane RTI-283^j 11u	C(=CH2)CH3	14.4 ± 0.3	3.13 ± 0.16	1330 ± 333	0.2	92.4
	para-trans-propenylphenyltropane RTI-296^i 11v	trans-CH=CHCH3	5.29 ± 0.53	11.4 ± 0.28	1590 ± 93	2.1	300
	para-allylphenyltropane 11x	CH2CH=CH2	32.8 ± 3.1	28.4 ± 2.4	2480 ± 229	0.9	75.6
	para-ethynylphenyltropane RTI-360 11y	C≡CH	1.2 ± 0.1	4.4 ± 0.4	83.2 ± 2.8	3.7	69.3
	para-propynylphenyltropane RTI-281^i 11z	C≡CCH3	2.37 ± 0.2	15.7 ± 1.5	820 ± 46	6.6	346
	para-cis-propenylphenyltropane RTI-304 11w	cis-CH=CHCH3	15 ± 1.2	7.1 ± 0.71	2,800^k ± 300	0.5	186.6^k
	para-(Z)-phenylethenylphenyltropane	cis-CH=CHPh	11.7 ± 1.12	—	—	—	—
	para-benzylphenyltropane	-CH2-Ph	526 ± 65	7,240 ± 390 (658 ± 35)	6670 ± 377 (606 ± 277)	13.7	12.6
	para-phenylethenylphenyltropane	CH2 ║ -C-Ph||474 ± 133||2,710 ± 800 (246 ± 73)||7,060 ± 1,760 (4,260 ± 1,060)||5.7||14.8|-|||para-phenylethylphenyltropane^l||-(CH2)2-Ph||5.14 ± 0.63||234 ± 26 (21.3 ± 2.4)||10.8 ± 0.3 (6.50 ± 0.20)||45.5||2.1|-|||para-(E)-phenylethenylphenyltropane^l RTI-436||trans–CH=CHPh||3.09 ± 0.75||335 ± 150 (30.5 ± 13.6)||1960 ± 383 (1180 ± 231)||108.4||634.3|-|||para-phenylpropylphenyltropane^l||-(CH2)3-Ph||351 ± 52||1,243 ± 381 (113 ± 35)||14,200 ± 1,800 (8,500 ± 1,100)||3.5||40.4|-|||para-phenylpropenylphenyltropane^l||-CH=CH-CH2-Ph||15.8 ± 1.31||781 ± 258 (71 ± 24)||1,250 ± 100 (759 ± 60)||49.4||79.1|-|||para-phenylbutylphenyltropane^l||-(CH2)4-Ph||228 ± 21||4,824 ± 170 (439 ± 16)||2,310 ± 293 (1,390 ± 177)||21.1||10.1|-| ||para-phenylethynylphenyltropane^l RTI-298^[4] ||–≡–Ph||3.7 ± 0.16||46.8 ± 5.8 (4.3 ± 0.53)||347 ± 25 (209 ± 15)||12.6||93.7|-| ||para-phenylpropynylphenyltropane^l^[5] ||–C≡C-CH2Ph||1.82 ± 0.42||13.1 ± 1.7 (1.19 ± 0.42)||27.4 ± 2.6 (16.5 ± 1.6)||7.1||15|-| ||para-phenylbutynylphenyltropane^l RTI-430||–C≡C(CH2)2Ph||6.28 ± 1.25||2180 ± 345 (198 ± 31)||1470 ± 109 (885 ± 66)||347.1||234|-| ||para-phenylpentynylphenyltropane^l||–C≡C-(CH2)3-Ph||300 ± 37||1,340 ± 232 (122 ± 21)||4,450 ± 637 (2,680 ± 384)||4.46||14.8|-| ||para-trimethylsilylethynylphenyltropane||—||—||—||—||—||—|-| ||para-hydroxypropynylphenyltropane||—||—||—||—||—||—|-| ||para-hydroxyhexynylphenyltropane^l||–C≡C-(CH2)4OH||57 ± 4||828 ± 29 (75 ± 2.6)||9,500 ± 812 (5,720 ± 489)||14.5||166.6|-| ||para-(thiophen-3-yl)phenyltropane Tamagnan||p-thiophene||12||0.017||189||0.001416||15.7|-| ||para-biphenyltropane 11aa||Ph||10.3 ± 2.6^f 29.4 ± 3.8^ɑ 15.6 ± 0.6||95.8 ± 36 (8.7 ± 3.3)||1,480 ± 269 (892 ± 162)||6.1||94.8|-| ||3β-2-naphthyltropane RTI-318 11bb||3β-2-naphthyl||0.51 ± 0.03 3.32 ± 0.08^f 3.53 ± 0.09^ɑ||0.80 ± 0.06 (0.07 ± 0.1)||21.1 ± 1.0 (12.7 ± 0.60)||1.5||41.3|-| ||para-bimethoxyphenyltropane 15||OCH2OCH3^h||—||—||—||—||—|} ^ɑ[<sup>3</sup>H]DA uptake displacement Ki value. ^b[<sup>3</sup>H]5-HT uptake displacement Ki value. ^c[<sup>3</sup>H]NE uptake displacement Ki value. ^d[<sup>3</sup>H]5-HT uptake to [<sup>3</sup>H]DA uptake ratio. ^e[<sup>3</sup>H]NE uptake to [<sup>3</sup>H]DA uptake ratio. ^fIC50 for displacement of [<sup>3</sup>H]cocaine. ^gValues from alternate data-set differing from that used in rest of table. ^hOriginal source (Scheme 4, page 931, 7th of article) name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: i.e. "methoxymethyl" versus "methoxymethoxy" ^iProtonated as the (-)—tartrate salt (isomer) ^jProtonated as the tartrate salt ^kWas cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867. However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1^[6] which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value. ^lWhereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the para-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to a 180° extension outward from the para area of the aryl of these type of ligands. (4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes Tamagnan (thiophene) analogues of para-phenyltropanes.! Compound structure! Alphanumeric code (name)! para-substitution! N8! SERT! DAT! NET! Selectivity SERT versus DAT! Selectivity SERT versus NET 1 (cocaine) (—)-Cocaine CH3 1050 89 3320 0.08 3.2 2 (β-CIT), (Iometopane) Iodo CH3 0.46 ± 0.06 0.96 ± 0.15 2.80 ± 0.40 2.1 6.1 (R,S-Citalopram) — — 1.60 16,540 6,190 10,338 3,869 4a 2-Thiophene CH3 0.15 ± 0.015 52 ± 12.8 158 ± 12 346 1,053 4b (Tamagnan) 3-Thiophene CH3 0.017 ± 0.004 12.1 ± 3 189 ± 82 710 11,118 4c 2-(5-Br)-Thiophene CH3 0.38 ± 0.008 6.43 ± 0.9 324 ± 19 17 853 4d 2-(5-Cl)-Thiophene CH3 0.64 ± 0.04 4.42 ± 1.64 311 ± 25 6.9 486 4e 2-(5-I)-Thiophene CH3 4.56 ± 0.84 22.1 ± 3.2 1,137 ± 123 4.9 249 4f 2-(5-NH2)-Thiophene CH3 64.7 ± 3.7 >10,000 >30,000 >155 >464 4g 2-(4,5-NO2)-Thiophene CH3 5,000 >30,000 >10,000 >6.0 >2.0 4h 3-(4-Br)-Thiophene CH3 4.02 ± 0.34 183 ± 69 >10,000 46 >2,488 5a 2-Thiophene H 0.11 ± 0.006 12.2 ± 0.9 75.3 ± 9.6 111 685 5b 3-Thiophene H 0.23 ± 0.02 6.4 ± 0.27 39 ± 0.8 28 170 (3′,4′-Disubstituted phenyl)-tropanes Compound (+ S. Singh's name) X (4′-para) Y (3′-meta) 2 Position config 8 DA 5-HT NE RTI-318 11bb β-naphthyl CO2Me β,β NMe 0.5 0.81 20 Dichloropane (RTI-111^ɑ) 17c Cl Cl CO2Me β,β NMe 0.79 3.13 18.0 RTI-88 [recheck] 17e NH2 I CO2Me β,β NMe 1.35 1329^c 320^c RTI-97 17d NH2 Br CO2Me β,β NMe 3.91 181 282 RTI-112^b 17b Cl Me CO2Me β,β NMe 0.82 10.5 36.2 RTI-96 17a F Me CO2Me β,β NMe 2.95 76 520 Et I CO2Me β,β NMe 21.3 2.96 1349 RTI-353 (EINT) Et I CO2Me β,β NH 331 0.69 148 Me I CO2Me β,β NH 5.98 1.06 74.3 Me I CO2Me β,β NMe 3.12 6.81 484 Meltzer^[7] catechol CO2Me β,β NMe >100 ? ? Meltzer OAc OAc CO2Me β,β NMe ? ? ? ^ɑas ·HCl (salt) ^bas ·HCl·2 H2O (salt) ^cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes! Compound ! Short Name (S. Singh)! R^2! R^1! DA! 5HT! NE! Selectivity 5-HTT/DAT! Selectivity NET/DAT meta-fluorophenyltropane 16a F H 23 ± 7.8 - - - - meta-chlorophenyltropane 16b Cl H 10.6 ± 1.8 - - - - meta-bromophenyltropane 16c Br H 7.93 ± 0.08^ɑ - - - - meta-iodophenyltropane 16d I H 26.1 ± 1.7 - - - - meta-tributylstannylphenyltropane 16e SnBu3 H 1100 ± 170 - - - - meta-ethynylphenyltropane C≡CH H - - - - - meta-methyl-para-fluorophenyltropane RTI-96 17a CH3 F 2.95 ± 0.58 - - - - meta-methyl-para-chlorophenyltropane RTI-112^c 17b CH3 Cl 0.81 ± 0.05 10.5 ± 0.05 36.2 ± 1.0 13.0 44.7 meta-para-dichlorophenyltropane RTI-111^b^[8] Dichloropane 17c Cl Cl 0.79 ± 0.08^b 3.13 ± 0.36^b 18.0 ± 0.8 17.96 ± 0.85^b'd 4.0^b 22.8^b meta-bromo-para-aminophenyltropane RTI-97 17d Br NH2 3.91 ± 0.59 181 282 46.2 72.1 meta-iodo-para-aminophenyltropane RTI-88 17e I NH2 1.35 ± 0.11 120 ± 4 1329 ± 124 88.9 984 meta-iodo-para-azidophenyltropane 17f I N3 4.93 ± 0.32 - - - - ^ɑIC50 determined in Cynomolgous monkey caudate-putamen ^bas ·HCl (salt) ^cas ·HCl·2 H2O (salt) ^dNEN 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropanes^[9] ! Structure ! Compound! R! X! n! Inhibition of [<sup>3</sup>H]WIN 35,428 @ DAT IC50 (nM)! Inhibition of [<sup>3</sup>H]Paroxetine @ 5-HTT Ki (nM)! Inhibition of [<sup>3</sup>H]Nisoxetine @ NET Ki (nM)! NET/DAT (uptake ratio)! NET/5-HTT (uptake ratio) Cocaine Des-thio/sulfinyl/sulfonyl H H Desmethyl 0 89.1 95 1990 22 21 para-methoxyphenyltropane Singh: 11i Des-thio/sulfinyl/sulfonyl OCH3 H 0 6.5 ± 1.3 4.3 ± 0.5 1110 ± 64 171 258 7a CH3 H 0 9 ± 3 0.7 ± 0.2 220 ± 10 24 314 7b C2H5 H 0 232 ± 34 4.5 ± 0.5 1170 ± 300 5 260 7c CH(CH3)2 H 0 16 ± 2 23 ± 2 129 ± 2 8 7 7d CF3 H 0 200 ± 70 8 ± 2 1900 ± 300 10 238 7e CH3 Br 0 10.1 ± 1 0.6 ± 0.2 121 ± 12 12 202 7f CH3 Br 1 76 ± 18 3.2 ± 0.4 690 ± 80 9 216 7g CH3 H 1 91 ± 16 4.3 ± 0.6 515 ± 60 6 120 7h CH3 H 2 >10,000 208 ± 45 >10,000 1 48 (2′,4′-Disubstituted phenyl)-tropanes Ortho-para-substituted (2′,4′-disubstituted phenyltropanes)! Compound structure ! Trivial IUPAC (non-systematic) Name! R^2 ortho! R^1 para! DA! 5HT! NE! Selectivity 5-HTT/DAT! Selectivity NET/DAT ortho,para-dinitrophenyltropane^[10] NO2 NO2 - - - - - (3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes Para-meta(3′)-meta(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes^[11] Para-methoxy/(ethoxy)-meta-substituted phenyltropanes! Structure ! Short Name (All compounds tested as HCl salts)! R^2 3′-(meta)! R^3 5′-(di-meta)! OR^1 4′-(para)! DAT IC50 [^3H](compound #)12! 5-HTT Ki [^3H]Paroxetine! NET Ki [^3H]Nisoxetine! Selectivity NET/DAT Ratio Ki/IC50! Selectivity NET/5-HTT Ratio Ki/Ki|-| || Cocaine||-||-||-||89.1||95||1990||22||21|-| || 6 RTI-112||-||-||-||0.82 ± 0.05||0.95 ± 0.04||21.8 ± 0.6||27||23|-| || 7a 11i || H || H ||CH3||6.5 ± 1.3||4.3 ± 0.5||1110 ± 64||171||258|-| || 7b || H || H || C2H5 ||92 ± 8||1.7 ± 0.4||1690 ± 50||18||994|-| || 7c || F || H || CH3 ||16 ± 1||4.8 ± 0.5||270 ± 50||17||56|-| || 7d || Br || H || CH3 ||47 ± 15||3.1 ± 0.1||160 ± 20||3||52|-| || 7f || Br || Br || CH3 ||92 ± 22||2.9 ± 0.1||4100 ± 400^ɑ||45||1413|-| || 7e || I || H || CH3 ||170 ± 60||3.5 ± 0.4||180 ± 20||1||51|-| || 7g || I || I || CH3 ||1300 ± 200||7.5 ± 0.8||180 ± 20||4||667|}^ɑN=2 (2′,4′,5′-Trisubstituted phenyl)-tropanes Ortho-para(4′)-meta(5′)-trisubstituted 2β-carbomethoxy-(2′,4′,5′-substituted phenyl)tropanes! Structure! Short Name! R^1 2′-(ortho)! R^2 4′-(para)! R^3 5′-(meta)! DAT! 5-HTT! NET! Selectivity NET/DAT Ratio! Selectivity NET/5-HTT Ratio para-ethyl-ortho, meta-diiodophenyltropane iodo ethyl iodo - - - - - 2-Carbmethoxy modified (replaced/substituted) General 2-carbmethoxy modifications 2β-substitutions of p-methoxy-phenyltropanes Para-OCH3-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues^[12] ! Structure ! Short Name (All compounds tested as HCl salts)! CO2R (2β-substituted) (compound 9 is 2β=R)! DAT IC50 [^3H](compound #)12! 5-HTT Ki [^3H]Paroxetine! NET Ki [^3H]Nisoxetine! Selectivity NET/DAT Ratio Ki/IC50! Selectivity NET/5-HTT Ratio Ki/Ki|-| || 7a 11i ||CH3||6.5 ± 1.3||4.3 ± 0.5||1110 ± 64||171||258|-| || 8a ||(CH3)2CH||14 ± 3||135 ± 35||2010 ± 200||144||15|-| || 8b ||cyclopropane||6.0 ± 2||29 ± 3||1230 ± 140||205||42|-| || 8c ||cyclobutane||13 ± 3||100 ± 8|| >3000 ||231||30|-| || 8d ||O2N...1,4-xylene...(CH2)2||42 ± 8||2.9 ± 0.2||330 ± 20||8||114|-| || 8e ||H2N...1,4-xylene...(CH2)2||7.0 ± 2||8.3 ± 0.4||2200 ± 300^ɑ||314||265|-| || 8f ||CH3CONH...1,4-xylene...(CH2)2||6.0 ± 1||5.5 ± 0.5||1460 ± 30||243||265|-| || 8g ||H2N...2-bromo-1,4-dimethylbenzene...(CH2)2||3.3 ± 1.4||4.1 ± 0.6||1850 ± 90||561||451|-| || 8h ||H2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)2||15 ± 6||2.0 ± 0.4||2710 ± 250^ɑ||181||1360|-| || 8i ||H2N...2-iodo-1,4-dimethylbenzene...(CH2)2||2.5 ± 0.7||3.5 ± 1||2040 ± 300^ɑ||816||583|-| || 8j ||H2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2||102 ± 15||1.0 ± 0.1||2600 ± 200^ɑ||25||2600|-| || 9 ||3-(4-methylphenyl)-1,2-oxazole||18 ± 6||860 ± 170||>3000||167||3|}^ɑN=2 2β-carboxy side-chained (p-chloro/iodo/methyl) phenyltropanes Multi-substituted structures of 2β-ester-3β-phenyltropanes! Compound ! Short Name (S. Singh)! R! X! IC50 (nM) DAT [<sup>3</sup>H]WIN 35428! IC50 (nM) 5-HTT [<sup>3</sup>H]paroxetine! IC50 (nM) NET [<sup>3</sup>H]nisoxetine! Selectivity 5-HTT/DAT! Selectivity NET/DAT 23a CH(CH3)2 H 85.1 ± 2.5 23121 ± 3976 32047 ± 1491 272 376 23b C6H5 H 76.7 ± 3.6 106149 ± 7256 19262 ± 593 1384 251 24a CH(CH3)2 Cl 1.4 ± 0.13 6.04 ± 0.31^ɑ 1400 ± 7 128 ± 15^b 778 ± 21 250 ± 0.9^c 1000 21.2^d 556 41.4^e 24b cyclopropyl Cl 0.96 ± 0.10 168 ± 1.8 235 ± 8.39 175 245 24c C6H5 Cl 1.99 ± 0.05 5.25 ± 0.76^ɑ 2340 ± 27 390 ± 34^b 2960 ± 220 242 ± 30^c 1176 74.3^d 1.3 41.6^e 24d C6H4-4-I Cl 32.6 ± 3.9 1227 ± 176 967.6 ± 26.3 37.6 29.7 24e C6H4-3-CH3 Cl 9.37 ± 0.52 2153 ± 143 2744 ± 140 230 293 24f C6H4-4-CH3 Cl 27.4 ± 1.5 1203 ± 42 1277 ± 118 43.9 46.6 24g C6H4-2-CH3 Cl 3.91 ± 0.23 3772 ± 384 4783 ± 387 965 1223 24h C6H4-4-Cl Cl 55 ± 2.3 16914 ± 1056 4883 ± 288 307 88.8 24i C6H4-4-OCH3 Cl 71 ± 5.6 19689 ± 1843 1522 ± 94 277 21.4 24j (CH2)2C6H4-4-NO2 Cl 2.71 ± 0.13 - - - - 24k (CH)2C6H4-4-NH2 Cl 2.16 ± 0.25 - - - - 24l (CH2)2C6H3-3-I-4-NH2 Cl 2.51 ± 0.25 - - - - 24m (CH2)2C6H3-3-I-4-N3 Cl 14.5 ± 0.94 - - - - 24n (CH2)2C6H4-4-N3 Cl 6.17 ± 0.57 - - - - 24o (CH2)2C6H4-4-NCS Cl 5.3 ± 0.6 - - - - 24p (CH2)2C6H4-4-NHCOCH2Br Cl 1.73 ± 0.06 - - - - 25a CH(CH3)2 I 0.43 ± 0.05 2.79 ± 0.13^ɑ 66.8 ± 6.53 12.5 ± 1.0^b 285 ± 7.6 41.2 ± 3.0^c 155 4.5^d 663 14.8^e 25b cyclopropyl I 0.61 ± 0.08 15.5 ± 0.72 102 ± 11 25.4 167 25c C6H5 I 1.51 ± 0.34 6.85 ± 0.93^ɑ 184 ± 22 51.6 ± 6.2^b 3791 ± 149 32.7 ± 4.4^c 122 7.5^d 2510 4.8^e 26a CH(CH3)2 CH3 6.45 ± 0.85 15.3 ± 2.08^ɑ 6090 ± 488 917 ± 54^b 1926 ± 38 73.4 ± 11.6^c 944 59.9^d 299 4.8^e 26b CH(C2H5)2 CH3 19.1 ± 1 4499 ± 557 3444 ± 44 235 180 26c cyclopropyl CH3 17.8 ± 0.76 485 ± 21 2628 ± 252 27.2 148 26d cyclobutyl CH3 3.74 ± 0.52 2019 ± 133 4738 ± 322 540 1267 26e cyclopentyl CH3 1.68 ± 0.14 1066 ± 109 644 ± 28 634 383 26f C6H5 CH3 3.27 ± 0.06 9.13 ± 0.79^ɑ 24500 ± 1526 1537 ± 101^b 5830 ± 370 277 ± 23^c 7492 168^d 1783 30.3^e 26g C6H4-3-CH3 CH3 8.19 ± 0.90 5237 ± 453 2136 ± 208 639 261 26h C6H4-4-CH3 CH3 81.2 ± 16 15954 ± 614 4096 ± 121 196 50.4 26i C6H4-2-CH3 CH3 23.2 ± 0.97 11040 ± 504 25695 ± 1394 476 1107 26j C6H4-4-Cl CH3 117 ± 7.9 42761 ± 2399 9519 ± 864 365 81.3 26k C6H4-4-OCH3 CH3 95.6 ± 8.8 82316 ± 7852 3151 ± 282 861 33.0 ^ɑKi value for displacement of [<sup>3</sup>H]DA uptake. ^bKi value for displacement of [<sup>3</sup>H]5-HT uptake. ^cKi value for displacement of [<sup>3</sup>H]NE uptake. ^d[<sup>3</sup>H]5-HT uptake to [<sup>3</sup>H]DA uptake ratio. ^e[<sup>3</sup>H]NE uptake to [<sup>3</sup>H]DA uptake ratio. Carboxyaryl Compound X 2 Position config 8 DA 5-HT NE I -CO2Ph β,β NMe 1.50 184 3,791 Cl -CO2Ph β,β NMe 1.98 2,336 2,955 NO2 -CO2Ph β,β NMe 5.94 2,910 5,695 RTI-120 [recheck] Me -CO2Ph β,β NMe 3.26 24,471 5,833 Cl -CO2(p-C6H4I) β,β NMe 33 1,227 968 Cl CO2(m-C6H4Me) β,β NMe 9.37 2153 2744 Cl -CO2(o-C6H4Me) β,β NMe 3.91 3,772 4,783 Me -CO2(m-C6H4Me) β,β NMe 8.19 5,237 2,137 RTI-206 Cl -CO2(p-C6H4Me) β,β NMe 27.4 1,203 1,278 2-Phenyl-3-Phenyltropanes 2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake! Compound Structure! Short Name (S. Singh)! Stereochemistry! X (para)! DAT [<sup>3</sup>H]WIN 35428 IC50 (nM)! DAT [<sup>3</sup>H]Mazindol Ki (nM)! 5-HTT [<sup>3</sup>H]Paroxetine IC50 (nM)! [<sup>3</sup>H]DA uptake Ki (nM)! [<sup>3</sup>H]5-HT uptake Ki (nM)! Selectivity [<sup>3</sup>H]5-HT/[<sup>3</sup>H]DA Cocaine (2β,3β) (H) 89 ± 4.8 281 1050 ± 89 423 155 0.4 67a 2β,3β H 12.6 ± 1.8 14.9 21000 ± 3320 28.9 1100 38.1 67b 2β,3α H - 13.8 - 11.7 753 64.3 67c 2α,3α H 690 ± 37 - 41300 ± 5300 - - - 68 2β,3α F - 6.00 - 4.58 122 26.6 69a 2β,3β CH3 1.96 ± 0.08 2.58 11000 ± 83 2.87 73.8 25.7 69b 2β,3α CH3 - 2.87 - 4.16 287 69.0 69c 2α,3α CH3 429 ± 59 - 15800 ± 3740 - - - Carboxyalkyl Code X 2 Position config 8 DA 5-HT NE RTI-77 Cl CH2C2(3-iodo-p-anilino) β,β NMe 2.51 — 2247 RTI-121 IPCIT I -CO2Pr^i β,β NMe 0.43 66.8 285 I -CO2Pr^i β,β NH 1.06 3.59 132 I -CO2Pr^cyc β,β NMe 0.61 15.5 102 Cl -CO2Pr^i β,β NMe 1.40 1,404 778 NO2 -CO2Pr^i β,β NMe 8.14 2,147 4,095 Cl -CO2Pr^cyc β,β NMe 0.96 168 235 Me -CO2Pr^cyc β,β NMe 1.68 1,066 644 Me -CO2Pr^i β,β NMe 6.45 6,090 1,926 Me -CO2Bu^cyc β,β NMe 3.74 2,020 4,738 Me -CO2C(H)Et2 β,β NMe 19 4500 3444 RTI-338 ethyl -CO2C2Ph β,β NMe 1104 7.41 3366 Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester. Use of a ^cycBu resulted in greater DAT selectivity than did the ^cycPr homologue. 2-Alkyl Esters & Ethers Esters (2-Alkyl) 2β-Alkyl Ester Phenyltropanes! Structure! Short Name (S. Singh)! 2β=R! Ki (nM) DAT [<sup>3</sup>H]WIN 35428! IC50 (nM) [<sup>3</sup>H]DA uptake! Selectivity uptake/binding 59a CH=CHCO2CH3 22 ± 2 123 ± 65 5.6 59b CH2CH2CO2CH3 23 ± 2 166 ± 68 7.2 59c (CH2)2CH=CHCO2CH3 20 ± 2 203 ± 77 10.1 59d (CH22)4CO2CH3 30 ± 2 130 ± 7 4.3 59e CH=CHCH2OH 26 ± 3 159 ± 43 6.1 59f CH2CH2CH2OH 11 ± 1 64 ± 32 5.8 59g CH2CH2COC6H5 28 ± 2 47 ± 15 1.7 Ethers (2-Alkyl) See the N-desmethyl Paroxetine homologues 2-Alkyl Ether Phenyltropanes! Molecular Structure! Short Name (S. Singh)! Stereochemistry! DAT [<sup>3</sup>H]WIN 35428 IC50 (nM)! 5-HTT [<sup>3</sup>H]Paroxetine IC50 (nM)! NET [<sup>3</sup>H]Nisoxetine IC50 (nM)! Selectivity 5-HTT/DAT! Selectivity NET/DAT Paroxetine 623 ± 25 0.28 ± 0.02 535 ± 15 0.0004 0.8 R-60a 2β,3β 308 ± 20 294 ± 18 5300 ± 450 0.9 17.2 R-60b 2α,3β 172 ± 8.8 52.9 ± 3.6 26600 ± 1200 0.3 155 R-60c 2β,3α 3.01 ± 0.2 42.2 ± 16 123 ± 9.5 14.1 40.9 S-60d 2β,3β 1050 ± 45 88.1 ± 2.8 27600 ± 1100 0.08 26.3 S-60e 2α,3β 1500 ± 74 447 ± 47 2916 ± 1950 0.3 1.9 S-60f 2β,3α 298 ± 17 178 ± 13 12400 ± 720 0.6 41.6 Carboxamides Structure Code (S. Singh #) X 2 Position config 8 DA [<sup>3</sup>H]WIN 35428 (IC50 nM) NE [<sup>3</sup>H]nisoxetine 5-HT [<sup>3</sup>H]paroxetine (IC50 nM) Selectivity 5-HTT/DAT Selectivity NET/DAT RTI-106 27b Cl CON(H)Me β,β NMe 12.4 ± 1.17 1584 ± 62 1313 ± 46 106 128 RTI-118 27a Cl CONH2 β,β NMe 11.5 ± 1.6 4270 ± 359 1621 ± 110 141 371 RTI-222 29d Me morpholinyl β,β NMe 11.7 ± 0.87 23601 ± 1156 >100K >8547 2017 RTI-129 27e Cl CONMe2 β,β NMe 1.38 ± 0.1 942 ± 48 1079 ± 102 792 683 RTI-146 27d Cl CONHCH2OH β,β NMe 2.05 ± 0.23 144 ± 3 97.8 ± 10 47.7 70.2 RTI-147 27i Cl CON(CH2)4 β,β NMe 1.38 ± 0.03 3,950 ± 72 12400 ± 1207 8985 2862 Cl CON(CH2)5 β,β NMe 6.61 5832 3468 Cl CON(H)CH2C≡CH β,β NMe 16.5 1839 4827 Cl CON(H)NH2 β,β NMe 44.1 3914 3815 Cl CONHCOMe β,β NMe 158 >43K >125K Cl CONHCH2COPh β,β NMe 7.79 1722 827 RTI-183✲ 27 g Cl CON(OMe)Me β,β NMe 0.85 ± 0.06 549 ± 18.5 724 ± 94 852 646 RTI-186 29c Me CON(OMe)Me β,β NMe 2.55 ± 0.43 422 ± 26 3402 ± 353 1334 165 RTI-198 27h Cl CON(CH2)3 β,β NMe 6.57 ± 0.67 990 ± 4.8 814 ± 57 124 151 RTI-196 27c Cl CONHOMe β,β NMe 10.7 ± 1.25 9907 ± 632 43700 ± 1960 4084 926 Cl CONHNHCOPh β,β NMe 91.8 >20K >48K RTI-208 27j Cl CONO(CH2)3 β,β NMe 1.47 ± 0.13 1083 ± 76 2470 ± 56 1680 737 RTI-214 27l Cl CON(-CH2CH2-)2O β,β NMe 2.90 ± 0.3 8545 ± 206 88769 ± 1855 30610 2946 RTI-215 27f Cl CONEt2 β,β NMe 5.48 ± 0.19 5532 ± 299 9433 ± 770 1721 1009 Cl CONH(m-C6H4OH) β,β NMe 4.78 >30K >16K RTI-218✲ Cl CON(Me)OMe β,β NMe 1.19 520 1911 RTI-226 27 m Cl CONMePh β,β NMe 45.5 ± 3 2202 ± 495 23610 ± 2128 519 48.4 I CONO(CH2)3 β,β NMe 0.75 446 230 RTI-229^[13] 28a I CON(CH2)4 β,β NMe 0.37 ± 0.04 991 ± 21 1728 ± 39 4670 2678 27k 6.95 ± 1.21 1752 ± 202 3470 ± 226 499 252 28b 1.08 ± 0.15 103 ± 6.2 73.9 ± 8.1 68.4 95.4 28c 0.75 ± 0.02 357 ± 42 130 ± 15.8 173 476 29a 41.8 ± 2.45 4398 ± 271 6371 ± 374 152 105 29b 24.7 ± 1.93 6222 ± 729 33928 ± 2192 1374 252 ✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same. 2β-Carboxamide-3β-Phenyltropanes! Compound! Short Name (S. Singh)! R! X! IC50 (nM) DAT [<sup>3</sup>H]WIN 35428! IC50 (nM) 5-HTT [<sup>3</sup>H]Paroxetine! IC50 (nM) NET [<sup>3</sup>H]Nisoxetine! Selectivity 5-HTT/DAT! Selectivity NET/DAT 29a NH2 CH3 41.8 ± 2.45 6371 ± 374 4398 ± 271 152 105 29b N(CH2CH3)2 CH3 24.7 ± 1.93 33928 ± 2192 6222 ± 729 1374 252 N(OCH3)CH3 CH3 2.55 ± 0.43 3402 ± 353 422 ± 26 1334 165 29d RTI-222 4-morpholine CH3 11.7 ± 0.87 >100000 23601 ± 1156 >8547 2017 Carboxamide linked phenyltropanes dimers Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo. Heterocycles These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize^[14] to the energetically more favorable trans configuration. This can happen to cocaine also.Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding. To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔVmin(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔVmin(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol. In contrast to this trend, it is understood that an increasingly negative ΔVmin is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand. 3-Substituted-isoxazol-5-yl N-methylphenyltropanes with 1R β,β stereochemistry.! Code (S.S. #)! X! R! DA! NE! 5HT Cl 3-methylisoxazol-5-yl 0.59 181 572 Me 3-methylisoxazol-5-yl 0.93 254 3818 I 3-methylisoxazol-5-yl 0.73 67.9 36.4 RTI-177 β-CPPIT 32g Cl 3-phenylisoxazol-5-yl 1.28 ± 0.18 504 ± 29 2420 ± 136 Me 3-phenylisoxazol-5-yl 1.58 398 5110 I 3-phenylisoxazol-5-yl 2.57 868 100 H methyl 43.3 — 6208 H Ph 285 — >12K Cl 3-ethylisoxazol-5-yl 0.50 120 3086 Cl isopropyl 1.19 954 2318 Cl 3-(4-methylphenyl)isoxazol-5-yl 4.09 1714 5741 Cl 3-t-butyl-isoxazol-5-yl 7.31 6321 37K Cl p-chlorophenyl 6.42 5290 >76K Cl p-anisyl 1.57 762 5880 Cl p-fluorophenyl 1.86 918 7257 RTI-354 Me 3-ethylisoxazol-5-yl 1.62 299 6400 RTI-366 Me R = isopropyl 4.5 2523 (1550) 42,900 (3900) RTI-371 Me p-chlorophenyl 8.74 >100K (60,200) >100K (9090) RTI-386 Me p-anisyl 3.93 756 (450) 4027 (380) RTI-387 Me p-fluorophenyl 6.45 917 (546) >100K (9400) 3-Substituted-1,2,4-oxadiazole Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.! Structure! Code (Singh's #)! X! R! DAT (IC50 nM) displacement of [H^3]WIN 35428! NET (IC50 nM) [H^3]nisoxetine! 5-HTT (IC50 nM) [H^3]paroxetine! Selectivity 5-HTT/DAT! Selectivity NET/DAT|-|||ααRTI-87|| H||3-methyl-1,2,4-oxadiazole||204||36K||30K|| |||-|||βαRTI-119|| H||3-methyl-1,2,4-oxadiazole||167||7K||41K|| |||-|||αβRTI-124 || H||3-methyl-1,2,4-oxadiazole||1028||71K||33K|| |||-|||RTI-125 (32a) || Cl ||3-methyl-1,2,4-oxadiazole||4.05 ± 0.57||363 ± 36||2584 ± 800||637||89.6|-|||ββRTI-126^[15] (31) || H ||3-methyl-1,2,4-oxadiazole||100 ± 6||7876 ± 551||3824 ± 420||38.3||788|-|||RTI-130 (32c) || Cl ||3-phenyl-1,2,4-oxadiazole||1.62 ± 0.02||245 ± 13||195 ± 5||120||151|-|||RTI-141 (32d)||Cl||3-(p-anisyl)-1,2,4-oxadiazole||1.81 ± 0.19||835 ± 8||337 ± 40||186||461|-|||RTI-143 (32e)||Cl||3-(p-chlorophenyl)-1,2,4-oxadiazole||4.06 ± 0.22||40270 ± 180 (4069)||404 ± 56||99.5||9919|-|||RTI-144 (32f)||Cl||3-(p-bromophenyl)-1,2,4-oxadiazole||3.44 ± 0.36||1825 ± 170||106 ± 10||30.8||532|-|||βRTI-151 (33)|| Me ||3-phenyl-1,2,4-oxadiazole||2.33 ± 0.26||60 ± 2||1074 ± 130||459||25.7|-|||αRTI-152|| Me ||3-phenyl-1,2,4-oxadiazole||494||—||1995|| |||-|||RTI-154 (32b)||Cl||3-isopropyl-1,2,4-oxadiazole||6.00 ± 0.55||135 ± 13||3460 ± 250||577||22.5|-|||RTI-155||Cl||3-cyclopropyl-1,2,4-oxadiazole||3.41||177||4362|| |||} N-methylphenyltropanes with 1R β,β stereochemistry.! Structure! Code! X! 2 Group! DAT (IC50 nM) displacement of [H^3]WIN 35428! NET (IC50 nM) displacement of [H^3]nisoxetine! 5-HTT (IC50 nM) displacement of [H^3]paroxetine! Selectivity 5-HTT/DAT! Selectivity NET/DAT|-|||RTI-157||Me||tetrazole||1557||>37K||>43K|| |||-|||RTI-163 || Cl ||tetrazole||911||—||5456|| |||-|||RTI-178 || Me ||5-phenyl-oxazol-2-yl||35.4||677||1699|| |||-|||RTI-188 || Cl ||5-phenyl-1,3,4-oxadiazol-2-yl||12.6||930||3304|| |||-|||RTI-189 (32i) || Cl ||5-phenyl-oxazol-2-yl||19.7 ± 1.98||496 ± 42||1120 ± 107||56.8||25.5|-|||RTI-194 || Me ||5-methyl-1,3,4-oxadiazol-2-yl||4.45||253||4885|| |||-|||RTI-195 || Me ||5-phenyl-1,3,4-oxadiazol-2-yl||47.5||1310||>22,000|| |||-|||RTI-199 || Me ||5-phenyl-1,3,4-thiadiazol-2-yl||35.9||>24,000||>51,000|| |||-|||RTI-200 || Cl ||5-phenyl-1,3,4-thiadiazol-2-yl||15.3||4142||>18,000|| |||-|||RTI-202 || Cl ||benzothiazol-2-yl||1.37||403||1119|| |||-|||RTI-219 || Cl ||5-phenylthiazol-2-yl||5.71||8516||10,342|| |||-| ||RTI-262||Cl|| ||188.2 ± 5.01||595.25 ± 5738||5207 ± 488||316||28|-|||RTI-370 || Me ||3-(p-cresyl)isoxazol-5-yl||8.74||6980||>100K|| |||-|||RTI-371 || Cl ||3-(p-chlorophenyl)isoxazol-5-yl||13||>100K||>100K|| |||-|||RTI-436||Me||-CH=CHPh^[16] ||3.09||1960 (1181)||335 (31)|| |||-|||RTI-470||Cl||o-Cl-benzothiazol-2-yl||0.094||1590 (994)||1080 (98)|| |||-|||RTI-451||Me||benzothiazol-2-yl||1.53||476 (287)||7120 (647)|| |||-|||32g|| || ||1.28 ± 0.18||504 ± 29||2420 ± 136||1891||394|-|||32h|| || ||12.6 ± 10.3||929 ± 88||330 ± 196||262||73.7|} N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan). Acyl (C2-propanoyl) (#) X Y 2 Position config 8 DA 5-HT NE WF-23 (39n) β-naphthyl C(O)Et β,β NMe 0.115 0.394 No data WF-31 PIT -Pr^i H C.O.Et β,β NMe 615 54.5 No data WF-11^✲ PTT (39e) Me H -C.O.Et β,β NMe 8.2 131 No data WF-25 (39a) H H -C.O.Et β,β NMe 48.3 1005 No data 6-MeoBN C(O)Et α,β NMe 0.13 2.24 No data ^✲Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration) 2β-acyl-3β-phenyltropane structures! Structure! S. Singh's alphanumeric assignation (name)! R1! R2! DAT[<sup>125</sup>I]RTI-55 IC50 (nM)! 5-HTT[<sup>3</sup>H]Paroxetine Ki (nM)! Selectivity5-HTT/DAT cocaine 173 ± 19 — — Troparil 11a (WIN 35065-2) 98.8 ± 12.2 — — WF-25 39a C2H5 C6H5 48.3 ± 2.8 1005 ± 112 20.8 39b CH3 C6H5 114 ± 22 1364 ± 616 12.0 39c C2H5 C6H4-4-F 15.3 ± 2.8 630 ± 67 41.2 39d CH3 C6H4-4-F 70.8 ± 13 857 ± 187 12.1 WF-11 39e C2H5 C6H4-4-CH3 8.2 ± 1.6 131 ± 1 16.0 (+)-39e C2H5 C6H4-4-CH3 4.21 ± 0.05 74 ± 12 17.6 (-)-39e C2H5 C6H4-4-CH3 1337 ± 122 >10000 — 39f CH3 C6H4-4-CH3 9.8 ± 0.5 122 ± 22 12.4 39g CH3 C6H4-4-C2H5 152 ± 24 78.2 ± 22 0.5 39h C2H5 C6H4-4-CH(CH3)2 436 ± 41 35.8 ± 4.4 0.08 39i C2H5 C6H4-4-C(CH3)3 2120 ± 630 1771 ± 474 0.8 39j C2H5 C6H4-4-C6H5 2.29 ± 1.08 4.31 ± 0.01 1.9 39k C2H5 C6H4-2-CH3 1287 ± 322 710000 >7.8 39l C2H5 1-naphthyl 5.43 ± 1.27 20.9 ± 2.9 3.8 39m CH3 1-naphthyl 10.1 ± 2.2 25.6 ± 5.1 2.5 WF-23 39n C2H5 2-naphthyl 0.115 ± 0.021 0.394 ± 0.074 3.5 39o CH3 2-naphthyl 0.28 ± 0.11 1.06 ± 0.36 3.8 39p C2H5 C6H4-4-CH(C2H5)2 270 ± 38 540 ± 51 2.0 39q C2H5 C6H4-4-C6H11 320 ± 55 97 ± 12 0.30 39r C2H5 C6H4-4-CH=CH2 0.90 ± 0.34 3.2 ± 1.3 3.5 39s C2H5 C6H4-4-C(=CH2)CH3 7.2 ± 2.1 0.82 ± 0.38 0.1 2β-Acyl-3β-naphthyl substituted 2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes^[17] ! Structure! Short Assignation (Numeric code, Davies UB) S. Singh! R! DAT [<sup>125</sup>H]RTI-55^ɑ IC50 nM! SERT [<sup>3</sup>H]paroxetine^b Ki nM! NET [<sup>3</sup>H]nisoxetine^c Ki nM! potency ratio SERT/DAT! potency ratio SERT/NET|-|||WF-11 (6)||4′-Me ||8.2 ± 1.6||131 ± 10||65 ± 9.2||0.06||0.5|-|||WF-31 (7)||4′-^iPr ||436 ± 41||36 ± 4||>10,000||12||>250|-|||WF-23 (8)||2-naphthalene ||0.12 ± 0.02||0.39 ± 0.07||2.9 ± 0.5||0.3||7|-|||2β-acyl-3β-1-naphthalene (9a)||4′-H||5.3 ± 1.3||21 ± 2.9||49 ± 10||0.3||18|-|||(9b)||4′-Me||25.1 ± 0.5||8.99 ± 1.70||163 ± 36||3||18|-|||(9c)||4′-Et||75.1 ± 11.9||175 ± 25||4769 ± 688||0.7||27|-|||(9d)||4′-^iPr||225 ± 36||136 ± 64||>10,000||2||>73.5|-|||(10a)||6′-Et ||0.15 ± 0.04||0.38 ± 0.19||27.7 ± 9.6||0.4||74|-|||(10b)||6′-^iPr||0.39 ± 0.04||1.97 ± 0.33||no data||0.2||—|-|||(10c^e)||6′- OMe||0.13 ± 0.04||2.24 ± 0.34||no data||0.05||—|-|||(10d)||5′-Et, 6′-OMe||30.8 ± 6.6||7.55 ± 1.57||3362 ± 148||4.1||445|-|||(10e)||5′-C(Me)=CH2, 6′-OMe||45.0 ± 3.7||88.0 ± 13.3||2334 ± 378||0.5||26.5|-|||(10f)||6′-I||0.35 ± 0.07||0.37 ± 0.02||no data||1.0||—|-|||(10g)||7′-I ||0.45 ± 0.05||0.47 ± 0.02||no data||0.5^d||—|-|||(10h)||5′-NO2, 6′-OMe||148 ± 50||15 ± 1.6||no data||10||—|-|||(10i)||5′-I, 6′-OMe ||1.31 ± 0.33||2.27 ± 0.31||781 ± 181||0.6||344|-|||(10j)||5′-COMe, 6′-OMe||12.6 ± 3.8||15.8 ± 1.65||498 ± 24||0.8||32|-|||(11a)||2β-COCH3, 1-naphthyl||10 ± 2.2||26 ± 5.1||165 ± 40||0.4||6.3|-|||(11b)||2α-COCH3, 1-naphthyl||97 ± 21||217 ± 55||no data||0.45||—|-|||(11c)||2α-COCH2CH3, 2-naphthyl||2.51 ± 0.82||16.4 ± 2.0||68.0 ± 10.8||0.15||4.1|-|||(11d)||2β-COCH3, 2-naphthyl||1.27 ± 0.15||1.06 ± 0.36||4.9 ± 1.2||1.2||4.6|-|||(11e)||2β-COCH(CH3)2, 2-naphthyl||0.25 ± 0.08||2.08 ± 0.80||37.6 ± 10.5||0.12||18.1|-|||(11f) 79a||2β-COCH2CH3, 2-naphthyl, N8-demethyl||0.03 ± 0.01||0.23 ± 0.07||2.05 ± 0.9||0.13||8.9|} ^ɑ nonspecific binding was determined in the presence of 1.0 μM WF-23 (source equates WF-23 as analogue 3a, but table gives # as analogue 8) ^b nonspecific binding was determined in the presence of 10.0 μM fluoxetine ^c nonspecific binding was determined in the presence of 1.0 μM desipramine ^d ratio shown as halved; a possible copy-error due to closeness to 1:1 of other indicated values ^e sources differ on whether C2 position acyl is alpha or beta configured Ester reduction Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate. Code X 2 Position config 8 DA 5-HT NE F -CH2OH β,β NMe 47 4741 no data I -CH2OH β,β NMe 2.2 26 no data Br -CH2OH β,β NMe 1.49 51 no data Cl -CH2OH β,β NMe 1.53 204 43.8 Cl -CH2OAc β,β NMe 1.60 143 127 Cl -CH2OBz β,β NMe 1.78 3.53 393 RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2.93 1.48 2-Alkane/Alkene 2-Alkane/Alkene-3-Phenyltropanes! Structure! Singh's #! R! X! DAT mazindol displacement! DA uptake! 5-HT Uptake! Selectivity DA uptake/DAT binding 11a WIN 35062-2 89.4 53.7 186 0.6 11c 0.83 ± 00.7 28.5 ± 0.9 — 34.3 11f 5.76 6.92 23.2 1.2 41a (CH2)2CH3 H 12.2 6.89 86.8 0.6 41b (CH2)3C6H5 H 16 ± 2^a 43 ± 13^b — 2.7 42 (CH2)2CH3 F 5.28 1.99 21.7 0.4 43a CH=CH2 Cl 0.59 ± 0.15 2.47 ± 0.5 — 4.2 43b E-CH=CHCl Cl 0.42 ± 0.04 1.13 ± 0.27 — 2.7 43c Z-CH=CHCl Cl 0.22 ± 0.02 0.88 ± 0.05 — 4.0 43d E-CH=CHC6H5 Cl 0.31 ± 0.04 0.66 ± 0.01 — 2.1 43e Z-CH=CHC6H5 Cl 0.14 ± 0.07 0.31 ± 0.09 — 2.2 43f CH2CH3 Cl 2.17 ± 0.20 2.35 ± 0.52 — 1.1 43 g (CH2)2CH3 Cl 0.94 ± 0.08 1.08 ± 0.05 — 1.1 43h (CH2)3CH3 Cl 1.21 ± 0.18 0.84 ± 0.05 — 0.7 43i (CH2)5CH3 Cl 156 ± 15 271 ± 3 — 1.7 43j (CH2)2C6H5 Cl 1.43 ± 0.03 1.54 ± 0.08 — 1.0 44a (CH2)2CH3 CH3 1.57 1.10 10.3 0.7 44b (CH2)3CH3 CH3 1.82 1.31 15.1 0.7 45 (CH2)2CH3 H 74.9 30.2 389 0.4 46 (CH2)2CH3 F 21.1 12.1 99.6 0.6 47a (CH2)2CH3 CH3 8.91 11.8 50.1 1.3 47b (CH2)3CH3 CH3 11.4 10.1 51.0 0.9 ^aKi value for displacement of WIN 35428. ^bIC50 value. Irreversible covalent (cf. ionic) C2 ligands Irreversible (phenylisothiocyanate) binding ligand (Murthy . V.. Martin . T. J.. Kim . S.. Davies . H. M. L.. Childers . S. R.. In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain. 10.1124/jpet.108.138842. Journal of Pharmacology and Experimental Therapeutics. 326. 2. 587–595. 2008. 18492949. 5996473.)^[18] RTI-76:^[19] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester. C2 Acyl, N8 phenylisothiocyanate HD-205 (Murthy et al., 2007)^[20] Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue. Benztropine based (C2-position hetero-substituted) phenyltropanes 2-(Diarylmethoxymethyl)-3β-aryltropanes & 2β-[3-(Diarylmethoxy)propyl]-3β-aryltropanes.^[21] ^[22] ! Structure! Compound! R! X! Y! [<sup>3</sup>H]WIN 35,428 @ DAT Ki (nM)! [<sup>3</sup>H]Citalopram @ SERT Ki (nM)! [<sup>3</sup>H]Nisoxetine @ NET Ki (nM)! [<sup>3</sup>H]Pirenzepine @ M1 Ki (nM)|-|rowspan=10||-| 9a ||CH3||H||H||34 ± 2||121 ± 19||684 ± 100||10,600 ± 1,100|-| 9b ||F||H||H||49 ± 12||—||—||—|-| 9c ||Cl||H||H||52 ± 2.1||147 ± 8||1,190 ± 72||11,000 ± 1,290|-| 9d ||CH3||Cl||H||80 ± 9||443 ± 60||4,400 ± 238||31,600 ± 4,300|-| 9e ||F||Cl||H||112 ± 11||—||—||—|-| 9f ||Cl||Cl||H||76 ± 7||462 ± 36||2,056 ± 236||39,900 ± 5,050|-| 9g ||CH3||F||F||62 ± 7||233 ± 24||1,830 ± 177||15,500 ± 1,400|-| 9h ||F||F||F||63 ± 13||—||—||—|-| 9i ||Cl||F||F||99 ± 18||245 ± 16||2,890 ± 222||16,300 ± 1,300|-|rowspan=7||-| 10a ||CH3||H||H||455 ± 36||530 ± 72||2,609 ± 195||12,600 ± 1,790|-| 10c ||Cl||H||H||478 ± 72||408 ± 16||3,998 ± 256||11,500 ± 1,720|-| 10d ||CH3||Cl||H||937 ± 84||1,001 ± 109||22,500 ± 2,821||18,200 ± 2,600|-| 10f ||Cl||Cl||H||553 ± 106||1,293 ± 40||5,600 ± 183||9,600 ± 600|-| 10g ||CH3||F||F||690 ± 76||786 ± 67||16,000 ± 637||9,700 ± 900|-| 10i ||Cl||F||F||250 ± 40||724 ± 100||52,300 ± 13,600||9,930 ± 1,090|-|rowspan=7||-| 12a ||H||H||H||139 ± 15||61 ± 9||207 ± 30||7,970 ± 631|-| 12b ||H||Cl||H||261 ± 19||45 ± 3||—||24,600 ± 2,930|-| 12c ||H||F||F||60 ± 7||—||—||—|} F&B series (Biotin side-chains etc.) One patent claims a series of compounds with biotin-related sidechains are pesticides. Structure Code para-X C2-Tropane Position config DA NE 5-HT — H F1 β,β — — — Me F1^c β,β 4.49 — 155.6 Me F2 β,β 4.38 516 73.6 Me F3^d β,β 1.75 402 72.4 — — F3 β,β — — — Me B1^d β,β 1.63 86.8 138 Me B2^d β,β 7.27 258 363 Me B3^d β,β 15.6 1809 33.7 Cl F4^c β,β 77.3 — — Me F4^c β,β 50.3 3000 — — — F5 β,β — — — Cl F6^c β,β 9.73 4674 6.96 Cl F1^c β,β 8.32 5023 81.6 Me F2 β,β 4.80 836 842 Me F7 wrong β,β 2.52 324 455 Me F7 right β,β 3.89 1014 382 Me F8 β,β 5.55 788 986 Miscellany (i.e. Misc./Miscellaneous) C2-substituents Structure Code X 2 Position config 8 DA 5-HT NE RTI-102 I CO2H β,β NMe 474 1928 43,400 RTI-103 Br CO2H β,β NMe 278 3070 17,400 RTI-104 F CO2H β,β NMe 2744 >100K >100K Cl -CH2Cl β,β NMe 2.64 98 129.8 Me -CH2CO2Me β,β NMe 1.02 619 124 Cl -CH3 β,β NMe 1.67 85 57 Cl -C≡N β,β NMe 13.1 1887 2516 Cl H3C–C=CH2 β,β NMe 1.28 57 141 Cl -CHMe2 β,β NMe 1.38 38.4 84.5 RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2,932 1,478 Me -C≡N β,β NMe 57 5095 1624 Me -CH2NH2 β,β NMe 10.5 855 120 Me -CH2NHMe β,β NMe 13.6 2246 280 Me -CH2NMe2 β,β NMe 3.48 206 137 Me -CHMe2 β,β NMe 0.61 114 35.6 Et -CO2CH2Ph β,β NMe 1104 7.41 3366 H -Ph β,β NMe 28.2 >34,000 2670 C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes) Aryl-Tropenes WO . 2004113297. Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors. 2004-12-29. NeuroSearch AS. Peters. Dan . Olsen. Gunnar M.. Nielsen. Elsebet Oestergaard . Scheel-Krueger. Joergen. Test compound DA-uptake IC50(μM) NA-uptake IC50(μM) 5-HT-uptake IC50(μM) - (+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene 0.26 0.028 0.010 - (+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene 0.058 0.013 0.00034 - (–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene 0.034 0.018 0.00023 Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM) (±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 18 4.9 0.047 (±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 1.5 0.5 0.016 (±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 22.00 8.00 0.0036 Enantioselective nonstandard configurations (non-2β-,3β-) β,α Stereochemistry Structure Compound (RTI #) (S. Singh's #) X 2 Group config 8 DAT IC50 (nM) [<sup>3</sup>H]WIN 35428 5-HTT IC50 (nM) [<sup>3</sup>H]paroxetine NET IC50 (nM) [<sup>3</sup>H]nisoxetine selectivity 5-HTT/DAT selectivity NET/DAT RTI-140 20a H CO2Me β,α NMe 101 ± 16 5,701 ± 721 2,076 ± 285 56.4 20.6 RTI-352^ɑ 20d I CO2Me β,α NMe 2.86 ± 0.16 64.9 ± 1.97 52.4 ± 4.9 22.8 18.4 Br CO2Me β,α NMe — — — — — RTI-319^b 3α-2-naphthyl CO2Me β,α NMe 1.1 ± 0.09 11.4 ± 1.3 70.2 ± 6.28 — — RTI-286^c 20b F CO2Me β,α NMe 21 ± 0.57 5062 ± 485 1231 ± 91 241 58.6 RTI-274^d F CH2O(3′,4′-MD-phenyl) β,α NH 3.96 5.62 14.4 — — Et CO2Me β,α NMe 327 1687 17,819 — — 20c Cl CO2Me β,α NMe 2.4 ± 0.2 998 ± 120 60.1 ± 2.4 416 25.0 20e Me CO2Me β,α NMe 10.2 ± 0.08 4250 ± 422 275 ± 24 417 27.0 Bn CO2Me β,α NMe — — — — — α,β Stereochemistry CA. 2112084. Compound DA (μM) M.E.D. (mg/kg) Dose (mg/kg) Activity Activity (2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane 0.39 <1 50 0 0 (2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane 0.1 1 25 0 0 (2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane 0.016 0.25 50 + +++ di-chloro; para- & meta- in tandem (α,β configured phenyltropanes) Compound X 2 Group config 8 DA 5-HT NE - Cl2 methyl aldoxime α,β NMe — — — - Cl2 ethoxymethyl α,β NMe 65 11 1.7 - NS-2359 (GSK-372,475) Cl2 Methoxymethyl α,β NH — — — fumaric acid salts (of α,β configured phenyltropanes) WO. 2004072075. Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors. 2004-08-26. NeuroSearch AS. Peters. Dan . Olsen. Gunnar M.. Nielsen. Elsebet Oestergaard . Scheel-Krueger. Joergen. Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM) (2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.062 0.035 0.00072 (2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.062 0.15 0.0063 (2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.10 0.048 0.0062 (2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.088 0.051 0.013 Arene equivalent alterations η^6-3β-(transition metal complexed phenyl)tropanes Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η^6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule. (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.^[23]). 21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity Ki values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand. Displacement of Receptor-Bound [<sup>3</sup>H]WIN 35428 and Inhibition of [<sup>3</sup>H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes! Structure! Compound # (S. Singh) Systematic name! Ki (nM)^ɑ! IC50 (nM)! selectivity binding/uptake 21a^c 17 ± 15^b 224 ± 83 418 24.6 21b^d 2280 ± 183 3890 1.7 Cocaine 32 ± 5 388 ±221 405 12.6 Troparil (11a) 33 ± 17 314 ± 222 373 11.3 ^ɑThe binding data fit a two-site model better than a one-site model ^bThe Ki value for the one-site model was 124 ± 10 nM ^cIUPAC: [η^6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium ^dIUPAC: [η^5-(pentamethylcyclopentadienyl)]-[η^6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate 3-(2-thiophene) and 3-(2-furan) Code Compound DA (μM) NE (μM) 5-HT (μM) 1 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt 0.30 0.0019 0.00052 2 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.36 0.0036 0.00042 3 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.31 0.00090 0.00036 4 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.92 0.0030 0.00053 5 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.074 0.0018 0.00074 6 (2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.19 0.0016 0.00054 Diaryl 6/7-tropane position substituted 2β-carbomethoxy 6/7 substituted 6/7-Substituted 2-carbomethoxy-phenyltropanes! Structure! Compound # (S. Singh)! Substitution! DAT (IC50 nM) displacement of [H<sup>3</sup>]WIN 35428! 5-HTT (IC50 nM) [H<sup>3</sup>]Citalopram! Selectivity 5-HTT/DAT Cocaine H 65 ± 12 - - 103a 3β,2β, 7-OMe 3′,4′-Cl2 86 ± 4.7 884 ± 100 10.3 103b 3β,2β, 7-OH 3′,4′-Cl2 1.42 ± 0.03 28.6 ± 7.8 20.1 103c 3α,2β, 7-OH 3′,4′-Cl2 1.19 ± 0.16 1390 ± 56 1168 104a 3β,2β, 6-OH 4′-Me 215^ɑ - - 104b 3β,2α, 6-OH 4′-Me 15310^ɑ - - 104c 3α,2β, 6-OH 4′-Me 930^ɑ - - 104d 3α,2α, 6-OH 4′-Me 7860^ɑ - - ^ɑIC50 value for displacement of [H<sup>3</sup>]mazindol. IC50 for cocaine 288 nM for displacement of [H<sup>3</sup>]mazindol 3-butyl 6/7 substituted 6/7-Substituted 3-butyl-phenyltropanes! Structure! Compound # (S. Singh)! Substituent! Ki nM displacement of [H<sup>3</sup>]mazindol binding! Ki nM [H<sup>3</sup>]DA uptake! Selectivity uptake/binding Cocaine H 270 ± 0.03 400 ± 20 1.5 121a 7β-CN 2020 ± 10 710 ± 40 0.3 121b 6β-CN 3040 ± 480 6030 ± 880 2.0 121c 7β-SO2Ph 4010 ± 310 8280 ± 1340 2.1 121d 6β-SO2Ph 4450 ± 430 8270 ± 690 1.8 121e 7α-OH 830 ± 40 780 ± 60 0.9 121f H 100 ± 10 61 ± 10 0.6 121g 7β-CN 24000 ± 3420 32100 ± 8540 1.3 121h 6β-CN 11300 ± 1540 26600 ± 3330 2.3 121i 7β-SO2Ph 7690 ± 2770 7050 ± 450 0.9 121j 6β-SO2Ph 4190 ± 700 8590 ± 1360 2.0 121k 7α-SO2Ph 3420 ± 1100 - - 121l 7β-SO2Ph, 7α-F 840 ± 260 2520 ± 290 3.0 121m 7α-F 200 ± 10 680 ± 10 3.4 121n 7β-F 500 ± 10 550 ± 140 1.1 intermediate 6- & 7-position synthesis modified phenyltropanes 6/7-synthetic intermediates! Structure! Compound # (S. Singh)! Substituent W! Substituent X! Substituent Y! Substituent Z (±)-122a CN H H H (±)-122b H H CH H (±)-122c H CH H H (±)-122d H H H CH (±)-122e SO2Ph H H H (±)-122f H H SO2Ph H (±)-122g H SO2Ph H H (±)-122h SO2Ph F H H (±)-122i F SO2Ph H H (±)-122j H H SO2Ph F 8-tropane (bridgehead) position modified Nortropanes (N-demethylated) NS2359 (GSK-372,475) It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.^[24] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.^[25] Selected ββ Nortropanes! Code (S.S. #)! X para ! DA! 5HT! NE RTI-142 75b F 4.39 68.6 18.8 RTI-98 75d Nor^ɑ-RTI-55 I 0.69 0.36 11.0 RTI-110 75c Cl 0.62 4.13 5.45 RTI-173 75f Et 49.9 8.13 122 RTI-279 Nor^ɑ-RTI-280 para-Me meta-I 5.98 ± 0.48 1.06 ± 0.10 74.3 ± 3.8 RTI-305 Nor^ɑ-RTI-360/11y Ethynyl 1.24 ± 0.11 1.59 ± 0.2 21.8 ± 1.0 RTI-307 Nor^ɑ-RTI-281/11z Propynyl 6.11 ± 0.67 3.16 ± 0.33 115.6 ± 5.1 RTI-309 Nor^ɑ-11t Vinyl 1.73 ± 0.05 2.25 ± 0.17 14.9 ± 1.18 RTI-330 Nor^ɑ-11s Isopropyl 310.2 ± 21 15.1 ± 0.97 — RTI-353 para-Et meta-I 330.54 ± 17.12 0.69 ± 0.07 148.4 ± 9.15 ^ɑThe N-demethylated variant of (i.e. compound code-name after dash) N-demethylating various β,β p-HC-phenyltropanes!N-Me compound code# → N-demethylated derivative compound code #!para-X![<sup>3</sup>H]Paroxetine![<sup>3</sup>H]WIN 35,428![<sup>3</sup>H]Nisoxetine 11 g→75f Ethyl 28.4 → 8.13 55 → 49.9 4,029 → 122 11t→75i Vinyl 9.5 → 2.25 1.24 → 1.73 78 → 14.9 11y→75n Ethynyl 4.4 → 1.59 1.2 → 1.24 83.2 → 21.8 11r→75 g 1-Propyl 70.4 → 26 68.5 → 212 3,920 → 532 11v→75k trans-propenyl 11.4 → 1.3 5.29 → 28.6 1,590 → 54 11w→75l cis-propenyl 7.09 → 1.15 15 → 31.6 2,800 → 147 11x→75 m Allyl 28.4 → 6.2 32.8 → 56.5 2,480 → 89.7 11z→75o 1-Propynyl 15.7 → 3.16 2.37 → 6.11 820 → 116 11s→75h i-Propyl 191 → 15.1 597 → 310 75,000 → ? 11u→75j 2-Propenyl 3.13 → 0.6 14.4 → 23 1,330? → 144 N-Demethylating phenyltropanes to find a NRI Isomer 4′ 3′ NE DA 5HT β,β Me H 60 → 7.2 1.7 → 0.84 240 → 135 β,β F H 835 → 18.8 15.7 → 4.4 760 → 68.6 β,β Cl H 37 → 5.45 1.12 → 0.62 45 → 4.13 β,α Me H 270 → 9 10.2 → 33.6 4250 → 500 β,α F H 1200 → 9.8 21 → 32.6 5060 → 92.4 β,α Cl H 60 → 5.41 2.4 → 3.1 998 → 53.3 β,α F Me 148 → 4.23 13.7 → 9.38 1161 → 69.8 β,α Me F 44.7 → 0.86 7.38 → 9 1150 → 97.4 "Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).^[26] N-norphenyltropanes! Structure! Short Name (S. Singh)! Para-X! DAT [<sup>3</sup>H]WIN 35428 IC50 (nM)! 5-HTT [<sup>3</sup>H]Paroxetine IC50 (nM)! NET [<sup>3</sup>H]Nisoxetine IC50 (nM)! Selectivity 5-HTT/DAT! Selectivity NET/DAT Norcocaine H 206 ± 29 127 ± 13 139 ± 9 0.6 0.7 75a H 30.8 ± 2.3 156 ± 8 84.5 ± 7.5 5.1 2.7 75b F 4.39 ± 0.20 68.6 ± 2.0 18.8 ± 0.7 15.6 4.3 75c Cl 0.62 ± 0.09 4.13 ± 0.62 5.45 ± 0.21 6.7 8.8 75d I 0.69 ± 0.2 0.36 ± 0.05 7.54 ± 3.19 0.5 10.9 75e para-I &<br />2β-CO2CH(CH3)2 1.06 ± 0.12 3.59 ± 0.27 132 ± 5 3.4 124 75f C2H5 49.9 ± 7.3 8.13 ± 0.30 122 ± 12 0.2 2.4 75g n-C3H7 212 ± 17 26 ± 1.3 532 ± 8.1 0.1 2.5 75h CH(CH3)2 310 ± 21 15.1 ± 0.97 - 0.05 - 75i CH=CH2 1.73 ± 0.05 2.25 ± 0.17 14.9 ± 1.18 1.3 8.6 75j C-CH3 ║ CH2||23 ± 0.9||0.6 ± 0.06||144 ± 12||0.03||6.3|-| || 75k ||trans-CH=CHCH3||28.6 ± 3.1||1.3 ± 0.1||54 ± 16||0.04||1.9|-| || 75l ||cis-CH=CHCH3||31.6 ± 2.2||1.15 ± 0.1||147 ± 4.3||0.04||4.6|-| || 75m ||CH2CH=CH2||56.5 ± 56||6.2 ± 0.3||89.7 ± 9.6||0.1||1.6|-| || 75n ||CH≡CH||1.24 ± 0.11||1.59 ± 0.2||21.8 ± 1.0||1.3||17.6|-| || 75o ||CH≡CCH3||6.11 ± 0.67||3.16 ± 0.33||116 ± 5.1||0.5||19.0|-| || 75p^ɑ||3,4-Cl2||0.66 ± 0.24||1.4^b||-||2.1||-|}^ɑThese values determined in Cynomolgus monkey caudate-putamen^bThe radioligand used for 5-HTT was [<sup>3</sup>H]citalopram 2β-Propanoyl-N-norphenyltropanes! Compound Structure! Short Name (S. Singh)! DAT [<sup>125</sup>I]RTI-55 IC50 (nM)! 5-HTT [<sup>3</sup>H]Paroxetine Ki (nM)! NET [<sup>3</sup>H]Nisoxetine Ki (nM)! Selectivity 5-HTT/DAT! Selectivity NET/DAT 79a 0.07 ± 0.01 0.22 ± 0.16 2.0 ± 0.09 3.1 28.6 79b 4.7 ± 0.58 19 ± 1.4 5.5 ± 2.0 4.0 1.2 79c 380 ± 110 5.3 ± 1.0 3400 ± 270 0.01 8.9 79d 190 ± 17 150 ± 50 5100 ± 220 0.8 26.8 79e 490 ± 120 85 ± 16 4300 ± 1100 0.1 8.8 79f 1.5 ± 1.1 0.32 ± 0.06 10.9 ± 1.5 0.2 7.3 79g 16 ± 4.9 0.11 ± 0.02 94 ± 18 0.07 5.9 Paroxetine homologues See the N-methyl paroxetine homologuescf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class. 2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies! Compound Structure! Short Name (S. Singh)! Stereochemistry! DAT [<sup>3</sup>H]WIN 35428 IC50 (nM)! 5-HTT [<sup>3</sup>H]Paroxetine IC50 (nM)! NET [<sup>3</sup>H]Nisoxetine IC50 (nM)! Selectivity 5-HTT/DAT! Selectivity NET/DAT Paroxetine - 623 ± 25 0.28 ± 0.02 535 ± 15 0.0004 0.8 R-81a 2β,3β 835 ± 90 480 ± 21 37400 ± 1400 0.6 44.8 R-81b 2α,3β 142 ± 13 90 ± 3.4 2500 ± 250 0.6 17.6 R-81c 2β,3α 3.86 ± 0.2 5.62 ± 0.2 14.4 ± 1.3 1.4 3.7 S-81d 2β,3β 1210 ± 33 424 ± 15 17300 ± 1800 0.3 14.3 S-81e 2α,3β 27.6 ± 2.4 55.8 ± 5.73 1690 ± 150 2.0 61.2 S-81f 2β,3α 407 ± 33 19 ± 1.8 1990 ± 176 0.05 4.9 N-replaced (S,O,C) The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy. Compound X 2 Group config 8 DA 5-HT NE - Cl,Cl CO2Me (racemic) β,β O 3.3 6.5 No data - O-4210^[27] p-F 3-methyl-5-isoxazole β,β S 7.0 >1000 No data 8-oxa bridgehead replacements 8-Oxanortropanes, binding inhibition using monkey caudate-putamen! Structure! Compound # (S. Singh)! Para- (meta-)! DAT (IC50 nM) displacement of [H^3]WIN 35428! 5-HTT (IC50 nM) [H^3]Citalopram! Selectivity 5-HTT/DAT|-| || R/S-90a ||H||>1000||>1000||-|-| || R/S-90b ||F||546||2580||4.7|-| || R/S-90c ||Cl||10||107||10.7|-| || R/S-90d ||Br||22||30||1.4|-| || R/S-90e ||I||7||12||1.7|-| || R/S-90f ||3,4-Cl2||3.35||6.52||1.9|-| || R-90g ||3,4-Cl2||3.27||4.67||1.4|-| || S-90h ||3,4-Cl2||47||58||1.2|-| || R/S-91a ||H||1990||11440||5.7|-| || R/S-91b ||F||>1000||>10000||-|-| || R/S-91c ||Cl||28.5||816||28.6|-| || R/S-91d ||Br||9||276||30.7|-| || R/S-91e ||I||42||72||1.7|-| || R/S-91f ||3,4-Cl2||3.08||64.5||20.9|-| || R-91g ||3,4-Cl2||2.34||31||13.2|-| || S-91h ||3,4-Cl2||56||2860||51.1|} 8-carba bridgehead replacements 8-carba 3-Aryl bicyclo[3.2.1]octanes! Structure! Compound # (S. Singh)! DAT (IC50 nM) displacement of [H^3]WIN 35428! 5-HTT (IC50 nM) [H^3]Citalopram! Selectivity 5-HTT/DAT|-||| R/S-98a ||7.1 ± 1.7||5160 ± 580||726|-||| R/S-98b ||9.6 ± 1.8||33.4 ± 0.6||3.5|-||| R/S-98c ||14.3 ± 1.1||180 ± 65||12.6|} N-alkyl Compound X 2 Group config 8 DAT SERT NET Cl 3′-phenylisoxazol-5′-yl β,β NCH2CH2CH2F - - - Cl (3′-phenylisoxazol-5′-yl) β,β NCH2CH2F - - - Altropane (IACFT) F CO2Me β,β NCH2CH=CHF - - - FECNT^[28] I CO2Me β,β NCH2CH2F - - - I CO2Me β,β N-Pr^n 1.17 - - I CO2Me β,β NCH2CH=CH2 1.79 - - I CO2Me β,β NBu^n 0.76 - - I CO2Me β,β NCH2CH2CH2F 1.67 - - Ioflupane (FP-CIT) ^123I CO2Me β,β NCH2CH2CH2F - - - PE2I Me CO2Me β,β NCH2CH=CHI - - - Cl CO2Me β,β NCH2CO2Et 1.93 10.1 114 Cl CO2Me β,β NCH2CH2CO2Et 2.56 35.2 125 Cl β,β (bridged) -C(O)CH(CO2Me)CH2N 7.67 227 510 Bi- and tri-cyclic aza compounds and their uses.^[29] N-substituted 3β-phenylnortropanes (including N-phthalimidoalkyl analogues of β-CIT)! Structure! Short Name (S. Singh)! Nitrogen side-chain (N8)! DAT [<sup>3</sup>H]GBR 12935 Ki (nM)! 5-HTT [<sup>3</sup>H]Paroxetine Ki (nM)! NET [<sup>3</sup>H]Nisoxetine Ki (nM)! Selectivity 5-HTT/DAT! Selectivity NET/DAT Cocaine H 350 ± 80 >10000 >30000 >28.6 - GBR 12909 - 0.06 ± 0.02 52.8 ± 4.4 >20000 880 - WIN 35428 11b H 14.7 ± 2.9 181 ± 21 635 ± 110 12.3 43.2 RTI-55 11e H 1.40 ± 0.20 0.46 ± 0.06 2.80 ± 0.40 0.3 2 82a CH2CH=CH2 22.6 ± 2.9^ɑ - - - - 82b CH2CH2CH3 43.0 ± 17.7^ɑ - - - - 82c CH2C6H5 58.9 ± 1.65^b 1073^c - 18.2 - 82d (CH2)3C6H5 1.4 ± 0.2^b 133 ± 7^c - 95.0 - 82e (CH2)5C6H5 3.4 ± 0.83^b 49.9 ± 10.2^c - 14.7 - 83a CH2CH2CH2F 1.20 ± 0.29 48.7 ± 8.4 10000 40.6 8333 83b CH2CH2F 4.40 ± 0.35 21.7 ± 8.3 >10000 4.9 - 84a CH2CH2CH2F 3.50 ± 0.39 0.110 ± 0.02 63.0 ± 4.0 0.03 18 84b CH2CH2F 4.00 ± 0.73 0.140 ± 0.02 93.0 ± 17.0 0.03 23.2 84c CH2CHF2 15.1 ± 3.7 9.6 ± 1.5 >5000 0.6 - 84d CH2CH2CH2Cl 3.10 ± 0.57 0.32 ± 0.06 96.0 ± 29.0 0.1 31.0 84e CH2CH2CH2Br 2.56 ± 0.57 0.35 ± 0.08 164 ± 47 0.1 64.1 84f CH2CH2CH2I 38.9 ± 6.3 8.84 ± 0.53 5000 0.2 128 84g CH2...methylcyclopropane 4.30 ± 0.87 1.30 ± 0.25 198 ± 9.6 0.3 46.0 84h CH2CH2CH2OH 5.39 ± 0.21 2.50 ± 0.20 217 ± 19 0.5 40.2 84i CH2CH2(OCH3)2 6.80 ± 1.10 1.69 ± 0.09 110 ± 7.7 0.2 16.2 84j CH2CO2CH3 11.9 ± 1.4 0.81 ± 0.10 29.1 ± 1.0 0.07 2.4 84k CH2CON(CH3)2 12.2 ± 3.8 6.40 ± 1.70 522 ± 145 0.5 42.8 84l CH2CH2CH2OMs 36.3 ± 2.1 17.3 ± 1.2 5000 0.5 138 84m COCH(CH3)2 2100 ± 140 102 ± 23 >10000 0.05 - 84n (CH2)2Pht 4.23 ± 0.48 0.84 ± 0.02 441 ± 66.0 0.2 104 84o (CH2)3Pht 9.10 ± 1.10 0.59 ± 0.07 74.0 ± 11.6 0.06 8.1 84p (CH2)4Pht 2.38 ± 0.22 0.21 ± 0.02 190 ± 18.0 0.09 79.8 84q (CH2)5Pht 2.40 ± 0.17 0.34 ± 0.03 60.0 ± 3.10 0.1 25.0 84r (CH2)8Pht 2.98 ± 0.30 0.20 ± 0.02 75.0 ± 3.6 0.07 25.2 84s^d CH2CH=CH-CH3 15 ± 1 75 ± 5 400 ± 80 5.0 26.7 84t^d CH2C(Br)=CH2 30 ± 5 200 ± 40 >1000 6.7 - 84u^d CH2CH=CH2I(E) 30 ± 5 960 ± 60 295 ± 33 32.0 9.8 84v^d CH2C≡CH 14 ± 1 100 ± 30 >1000 7.1 - 84w^d CH2C6H5 42 ± 12 100 ± 17 600 ± 100 2.4 14.3 84x^d CH2C6H4-2-CH3 93 ± 19 225 ± 40 >1000 2.4 - 85a^d para-H 113 ± 41 100 ± 20 >1000 0.9 - 85b^d para-Cl, meta-Cl 29 ± 4 50 ± 6 500 ± 120 1.7 17.2 85c^d para-Me 17 ± 7 500 ± 30 >1000 29.4 - 85d^d para-CH(CH3)2 500 ± 120 450 ± 80 >1000 0.9 - 85e^d para-n-C3H7 500 ± 100 300 ± 12 750 ± 160 0.6 1.5 ^ɑIC50 for displacement of [<sup>3</sup>H]cocaine. IC50 for cocaine = 67.8 ± 8.7 (nM) ^bIC50 values for displacement of [<sup>3</sup>H]WIN 35428 ^cIC50 values for displacement of [<sup>3</sup>H]citalopram ^dThe standard Ki value for the displacement of [<sup>3</sup>H]GBR 12935, [<sup>3</sup>H]paroxetine, and [<sup>3</sup>H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments 3β-(4-alkylthiophenyl)nortropanes! Structure ! Compound! R1! R2! Inhibition of [<sup>3</sup>H]WIN 35,428 @ DAT IC50 (nM)! Inhibition of [<sup>3</sup>H]Paroxetine @ 5-HTT Ki (nM)! Inhibition of [<sup>3</sup>H]Nisoxetine @ NET Ki (nM)! NET/DAT (uptake ratio)! NET/5-HTT (uptake ratio) See 7a—7h table 7a CH3 CH3 9 ± 3 0.7 ± 0.2 220 ± 10 24 314 7b C2H5 CH3 232 ± 34 4.5 ± 0.5 1170 ± 300 5 260 8a CH3 H 28 ± 6 0.19 ± 0.01 21 ± 6 0.8 110 8b C2H5 H 177 ± 62 1.26 ± 0.05 118 ± 13 0.7 94 9a CH3 FCH2CH2CH2 112 ± 2 3 ± 1 960 ± 100 9 320 9b C2H5 FCH2CH2CH2 1,200 ± 200 27 ± 2 >2,000 2 74 10a CH3 CH2=CH2CH2 71 ± 25 5.5 ± 0.8 2,000 ± 500 28 364 10b C2H5 CH2=CH2CH2 1,100 ± 100 47 ± 3 >2,000 2 43 11a CH3 CH3CH2CH2 74 ± 20 5.7 ± 0.6 1,200 ± 140 16 211 11b C2H5 CH3CH2CH2 900 ± 300 49 ± 6 >2,000 2 41 Bridged N-constrained phenyltropanes (fused/tethered) See: Bridged cocaine derivatives & N8 Tricyclic (2β—crossed-over) N8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues p-methyl aryl front & back N-bridged phenyltropanes Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes Ki (nM)!Compound # (S. Singh's #)!2β=R![<sup>3</sup>H]Mazindol binding![<sup>3</sup>H]DA uptake![<sup>3</sup>H]5-HT uptake![<sup>3</sup>H]NE uptake!selectivity [<sup>3</sup>H]5-HT/[<sup>3</sup>H]DA cocaine CO2CH3 375 ± 68 423 ± 147 155 ± 40 83.3 ± 1.5 0.4 (–)-40 (–)-128 54.3 ± 10.2 60.3 ± 0.4 1.76 ± 0.23 5.24 ± 0.07 0.03 (+)-40 (+)-128 79 ± 19 114 ± 28 1.48 ± 0.07 4.62 ± 0.31 0.01 (±)-40 (±)-128 61.7 ± 8.5 60.3 ± 0.4 2.32 ± 0.23 2.69 ± 0.12 0.04 29β 620 1420 8030 — — 30β 186 492 97.7 — — 31β 47.0 211 28.5 — — 29α 4140 20100 3920 — — 30α 3960 8850 696 1150 — 45 129 6.86 ± 0.43 24.0 ± 1.3 1.77 ± 0.04 1.06 ± 0.03 0.07 42a 131a n-Bu 4.00 ± 0.07 2.23 ± 0.12 14.0 ± 0.6 2.99 ± 0.17 6.3 41a 130a n-Bu 17.2 ± 1.13 10.2 ± 1.4 78.9 ± 0.9 15.0 ± 0.4 7.8 42b 131b Et 3.61 ± 0.43 11.3 ± 1.1 25.7 ± 4.3 4.43 ± 0.01 2.3 50a 133a n-Bu 149 ± 6 149 ± 2 810 ± 80 51.7 ± 12 5.4 49a 132a n-Bu 13.7 ± 0.8 14.2 ± 0.1 618 ± 87 3.84 ± 0.35 43.5 (–)-4 10500 16500 1890 70900 — (+)-4 18500 27600 4630 38300 — (–)-5 9740 9050 11900 4650 — (+)-5 6770 10500 25100 4530 — RTI-4229/Coc-242 N8/2β-C(O)CH(CO2Me)CH2N para-chloro — 7.67 ± 0.31^ɑ 226.54 ± 27.37^b 510.1 ± 51.4^c — ^ɑValue for displacement of [<sup>3</sup>H]WIN 35,428 binding @ DAT ^bValue for displacement of [<sup>3</sup>H]paroxetine binding to SERT ^cValue for displacement of [<sup>3</sup>H]nisoxetine from NET Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130—133) preferred placement with DAT interaction. 3,4-Cl2 aryl front-bridged phenyltropanes Code Compound DA (μM) NE (μM) 5-HT (μM) 1 (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.0<sup>4,8</sup>]- undecan-11 -one O-methyl-oxime 0.012 0.0020 0.0033 2 (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.0<sup>4,8</sup>]- undecan-11-one 0.18 0.035 0.0075 3 (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime 0.0160 0.0009 0.0032 4 (1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol 0.0750 0.0041 0.0028 5 (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one 0.12 0.0052 0.0026 6 (1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol 0.25 0.0074 0.0018 7 (1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate 0.21 0.0061 0.0075 8 (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane 0.022 0.0014 0.0001 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes. 2° amine is reacted with Br(CH2)nCO2Et. Base used to abstract proton α- to CO2Et group and complete the tricyclic ring closure step (Dieckmann cyclization). To make a different type of analog (see Kozikowski patent above) Remove N-Me Add ɣ-bromo-chloropropane Allow for cyclization with K2CO3 base and KI cat. C2 + C3 (side-chain) fused (carboxylate & benzene conjoined) (1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.0^2,^10.0^4,^9)pentadeca-4(9),5,7-trien-3-one C3 to 1′ + 2′ (ortho) tropane locant dual arene bridged Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the Endo–exo isomerism of their structures.^[30] Cycloalkane-ring alterations of the tropane ring system Azanonane (outer ring extended) 3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs. Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol. Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below. [3.3.1]azanonane analogues displacement of bound [<sup>3</sup>H]WIN 35428! Structure! Compound # (S. Singh)! Ki (nM) Cocaine 32 ± 5 390 ± 220 WIN 35065-2 33 ± 17 310 ± 220 146a 4600 ± 510 146b 5730 ± 570 146c 3450 ± 310 146d 3470 ± 350 147 13900 ± 2010 Azabornane (outer ring contracted) 3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.

Notes and References

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