List of cocaine analogues explained

This is a list of cocaine analogues. A cocaine analogue is an (usually) artificial construct of a novel chemical compound from (often the starting point of natural) cocaine's molecular structure, with the result product sufficiently similar to cocaine to display similarity in, but alteration to, its chemical function. Within the scope of analogous compounds created from the structure of cocaine, so named "cocaine analogues" retain 3β-benzoyloxy or similar functionality (the term specifically used usually distinguishes from phenyltropanes, but in the broad sense generally, as a category, includes them) on a tropane skeleton, as compared to other stimulants of the kind. Many of the semi-synthetic cocaine analogues proper which have been made & studied have consisted of among the nine following classes of compounds:

stereoisomers of cocaine
3β-phenyl ring substituted analogues
2β-substituted analogues
N-modified analogues of cocaine
3β-carbamoyl analogues
3β-alkyl-3-benzyl tropanes
6/7-substituted cocaines
6-alkyl-3-benzyl tropanes
piperidine homologues of cocaine

However strict analogues of cocaine would also include such other potential combinations as phenacyltropanes & other carbon branched replacements not listed above. The term may also be loosely used to refer to drugs manufactured from cocaine or having their basis as a total synthesis of cocaine, but modified to alter their effect & QSAR. These include both intracellular sodium channel blocker anaesthetics and stimulant dopamine reuptake inhibitor ligands (such as certain, namely tropane-bridged-excised, piperidines). Additionally, researchers have supported combinatorial approaches for taking the most promising analogues currently elucidated and mixing them to the end of discovering novel & efficacious compounds to optimize their utilization for differing distinct specified purposes.

Analogs sensu stricto

Cocaine Stereoisomers

Stereoisomer	S. Singh's alphanumeric assignation	IC₅₀ (nM) [<sup>3</sup>H]WIN 3542 inhibition to rat striatal membranes Mean error standard ≤5% in all cases	IUPAC nomenclature
R-cocaine (Erythroxyline)		102	methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-pseudococaine (Delcaine, Depsococaine, Dextrocaine, Isococaine, Psicaine.^[1])	172	15800	methyl(1R,2S,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
	R-allococaine	173	6160	methyl(1R,2R,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-allopseudococaine	174	28500	methyl(1R,2S,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
S-cocaine	175	15800	methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-pseudococaine	176	22500	methyl(1S,3R,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allococaine	177	9820	methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allopseudococaine	178	67700	methyl(1S,3S,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate

There are eight stereoisomers of cocaine (excluding mesomers and modifications to the internal portion of the tropane ring). Due to the presence of four asymmetric carbon atoms in the 1- & 5- to 8 (N) position bond bridge that could adopt R- & S- configurations, cocaine can be considered to have as many as sixteen stereoisomers. However, geometric constraints imparted by the bridgehead amine allow only eight to be created.

The natural isomerism of cocaine is unstable and prone to epimerization. For example, the end product of cocaine biosynthesis contains an axial C2-carbomethoxy moiety which readily undergoes epimerization to the equatorial position via saponification.

For any 2D structural diagrams where stereochemistry is not indicated, it should be assumed the analogue depicted shares the stereochemical conformation of R-cocaine unless noted otherwise.

Arene benzene-ring 2′, 3′, 4′ (5′ & 6′) position (aryl) substitutions

para-substituted benzoylmethylecgonines

Carbon 4′-hydrogen Substitutions (benzene-4′ "*para*" substituted benzoyloxytropanes)
^{Data-set congruent to, and aggregate with, following tables
IC₅₀ values}! Structure! S. Singh's
alphanumeric
assignation
(name)! 4′=R! DAT[<sup>3</sup>H]WIN 35428! 5-HTT[<sup>3</sup>H]Paroxetine! NET[<sup>3</sup>H]Nisoxetine! Selectivity5-HTT/DAT! SelectivityNET/DAT
	Cocaine	H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0
non-benzoyloxy analogue comparative ligands	11b (WIN 35428) _(nisoxetine) ^(fluoxetine)	F _— ^—	24 ± 4 _{775 ± 20} ^{5200 ± 1270}	690 ± 14 _{762 ± 90} ^{15 ± 3}	258 ± 40 _{135 ± 21} ^{963 ± 158}	28.7 _1.0 ^0.003	10.7 _0.2 ^0.2

	183a		2522 ± 4	1052 ± 23	18458 ± 1073	0.4	7.3
	183b		486 ± 63	-	-	-	-
	183c		144 ± 2	-	-	-	-
	183d		158 ± 8	3104 ± 148	601 ± 11	19.6	3.8
	(4′-Fluorococaine)^[2]		-	-	-	-	-
	(para-Isothiocyanatobenzoylecgonine methyl ester)^[3] (p-Isococ)		-	-	-	-	-

The MAT binding pocket analogous to the lipophilic place on cocaine-like compounds, inclusive of the benzene ring, is approximate to 9 Å in length. Which is only slightly larger than a phenyl ring by itself.

meta-substituted benzoylmethylecgonines

Carbon 3′-hydrogen Substitutions (benzene-3′ "*meta*" substituted benzoyloxytropanes)
^{Data-set congruent to, and aggregate with, preceding and following tables
IC₅₀ values}! Structure! S. Singh's
alphanumeric
assignation
(name)! 3′=R! DAT[<sup>3</sup>H]WIN 35428! 5-HTT[<sup>3</sup>H]Paroxetine! NET[<sup>3</sup>H]Nisoxetine! Selectivity5-HTT/DAT! SelectivityNET/DAT
(cocaine)	H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0

184a	I	325^ɑ	-	-	-	-
184b	OH	1183 ± 115	793 ± 33	3760 ± 589	0.7	3.2
191		-	-	-	-	-
(m-Isococ)		-	-	-	-	-

^ɑIC₅₀ value for displacement of [3H]cocaine

ortho-substituted benzoylmethylecgonines

Carbon 2′-hydrogen Substitutions (benzene-2′ "*ortho*" substituted benzoyloxytropanes)
^{Data-set congruent to, and aggregate with, preceding and following tables
IC₅₀ values}! Structure! S. Singh's
alphanumeric
assignation
(name)! 2′=R! DAT[<sup>3</sup>H]WIN 35428! 5-HTT[<sup>3</sup>H]Paroxetine! NET[<sup>3</sup>H]Nisoxetine! Selectivity5-HTT/DAT! SelectivityNET/DAT
Cocaine	H	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0

185a	I	350^ɑ	-	-	-	-
185b	F	604 ± 67	1770 ± 309	1392 ± 173	2.9	2.3
185c (2′-Acetoxycocaine)^[4]	OAc	70 ± 1	219 ± 20	72 ± 9	3.1	1.0
185d (2′-Hydroxycocaine)^[5]	OH	25 ± 4	143 ± 21	48 ± 2	5.7	1.9

^ɑIC₅₀ value for displacement of [3H]cocaine

The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.

Manifold and termination benzoyloxy phenyl-substitutions

Multi-substitutions (substitutions of substitutions; e.g. meta- & para-) or manifold ("many-fold") substituted analogues are analogues where more than one modification from the parent molecule takes place (having numerous intermediary constituents). These are created with often surprising structure–activity relationship results extrapolated therefrom. It is even a common case where two separate substitutions can each yield a weaker, lower affinity or even wholly non-efficacious compound respectively; but due to findings that oftentimes, when used together, such two mutually inferior changes being added in tandem to one analogue has the potential to make the resultant derivative display much greater efficacy, affinity, selectivity &/or strength than even the parent compound; which otherwise was compromised by either of those two alternations when made alone.

Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple benzene-2′,3′ & 4′ combined substituted benzoyloxytropanes)
^{Data-set (excepting instanced references inside table) congruent to, and aggregate with, preceding and following tables
IC₅₀ values}! Structure! S. Singh's
alphanumeric
assignation
(name)! *ortho*-2′=R! *meta*-3′=R! *para*-4′=R! DAT[<sup>3</sup>H]WIN 35428! 5-HTT[<sup>3</sup>H]Paroxetine! NET[<sup>3</sup>H]Nisoxetine! Selectivity5-HTT/DAT! SelectivityNET/DAT
	186	HO	H	I	215 ± 19	195 ± 10	1021 ± 75	0.9	4.7
	(Vanillylmethylecgonine)^[6]	H		OH	-	-	-	-	-

Terminating Phenyl Carbon Ring Fusions & Alterations
^{Data-set congruent to, and aggregate with, preceding table
IC₅₀ values}! Structure! S. Singh's
alphanumeric
assignation
(name)! C=R! DAT[<sup>3</sup>H]Cocaine (IC₅₀)
	187	1-naphthalene	742 ± 48
	188	2-naphthalene	327 ± 63

Benzoyl and carbomethoxy branch modifications

Benzoylthiomethylecgonine^[7]

A sulfur in place of the oxygen at the benzoyl ester single bond results in a lower electronegativity than that of cocaine.

Cocaine reverse ester (REC)^[8]

REC is a cocaine analogue which contains a "reversed" C2 carbomethoxy moiety. In animal studies, REC lacked cocaine-like stimulant effects.

C1-tropane-ring hydrogen—substitutions

C1 substitutions^[9]
K_i values for uptake inhibition obtained on HEK-293 heterologously expressed human monoamine transporter cells.^[10] ! Structure! Trivial name! R
(C1 moiety)! K_i (nM) @ DAT! K_i (nM) @ SERT! K_i (nM) @ NET! σ₁ affinity
K_i! σ₂ affinity
K_i! IC₅₀ (μM) Na+ inhibition
(Vertridine-Stimulated
influx of sodium channels
in Neocortical neurons)^c! LogP
(XLogP3 algorithm, Cheng et al., 2007)
(—)-Cocaine	H	326 ± 106	513 ± 143	358 ± 69	6.7 ± 0.3 μM^d^[11]	"significant"^[12]	6.99 ± 2.43	2.30
(—)-1-methyl-cocaine	Me	163 ± 23	435 ± 77	488 ± 101	"unappreciable"	1.13 μM	16.01 ± 1.90	2.67
(—)-1-ethyl-cocaine	Et	95.1 ± 17.0^ɑ	1,106 ± 112	598 ± 179	—	—	—	3.20
(—)-1-n-propyl-cocaine	n-Pr	871 ± 205^ɑ	2,949 ± 462^b	796 ± 195	—	—	—	3.56
(—)-1-n-pentyl-cocaine	n-C₅H₁₁	1,272 ± 199^b	1,866 ± 400^ɑ	1,596 ± 21^b	—	—	—	4.64
(—)-1-phenyl-cocaine	Ph	32.3 ± 5.7^b	974 ± 308	1,980 ± 99^b	524 nM	198 nM	0.29 ± 0.07	3.77

^ɑ, P < 0.05 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
^b, P < 0.01 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
^cLidocaine was found to have a value of 39.6 ± 2.4, the weakest of all tested.
^dSame reference gives 25.9 ± 2.4 μM for (+)-cocaine and 13.6 ± 1.3 μM for norcocaine. Comparably it gives 12.7 ± 1.5 μM for the sigmaergic affinity of (+)-amphetamine. Another reference gives 1.7-6.7 μM for (—)-cocaine. All values K_i.^[13]
Using same data-set as above table, the following compounds were found to compare as:
- CFT @ DAT = 39.2 ± 7.1 (n = 5)
- fluoxetine @ SERT = 27.3 ± 9.2 (n = 3)
- desipramine @ NET = 2.74 ± 0.59 (n = 3)

Cocaine analogs substituting the C1-tropane ring position, requiring sulfinimine (N-sulfinyl-imine) chemistry (before the innovation of which were untenable) which bind unlike the typical configuration at DAT (open to out) as cocaine (with its terminal D79-Y156 distance of 6.03 Å), or in the atypical (closed to out) conformation of the benztropines (3.29 Å). Though closer to the open to out: (—)-1-methyl-cocaine = 4.40 Å & (—)-1-phenyl-cocaine = 4.89 Å, and exhibiting preferential interaction with outward facing DAT conformation, they appear to have the lack of behavioral stimulation as-like the closed to out type. Despite having non-stimulant behavior profiles, they still seem to have anti-depressant behavioral profiles.^[10]

The C1 phenyl analog is ten times stronger than cocaine as a dopamine reuptake pump ligand, and twenty four times stronger as a local anesthetic (voltage-dependent Na+ channel blocker), whereas the C1 methyl analog is 2.3 times less potent as a local anesthetic.^[10]

cf. hydroxytropacocaine for a natural alkaloid (lacking however, the 2-position carbmethoxy) that is a C1 substituent with a hydroxy group.

2β-substitutions

Direct 2β Substitutions
^{(IC₅₀ nM values)}! Structure! S. Singh's
alphanumeric
assignation
(name)! R! DAT[<sup>3</sup>H]WIN 35428! 5-HTT[<sup>3</sup>H]Paroxetine! NET[<sup>3</sup>H]Nisoxetine! Selectivity5-HTT/DAT! SelectivityNET/DAT

(Cocaine)		89 ± 4.8	1045 ± 89	3298 ± 293	11.7	37.0
196a (Cocaethylene)		195 ± 45	5801 ± 493	10000 ± 751	29.7	51.3
196b	n-Pr	196 ± 46	4517 ± 430	6124 ± 262	23.3	31.2
196c	i-Pr	219 ± 48	25224 ± 1498	30384 ± 1685	115	139
196d	Ph	112 ± 31	33666 ± 3330	31024 ± 1909	300	277
196e	Bn	257 ± 14	302 ± 23	20794 ± 950	1.2	80.9
196f	β-phenethyl	181 ± 10	615 ± 52	19944 ± 1026	3.4	110
196g	γ-phenylpropyl	147 ± 19	374 ± 15	4893 ± 344	2.5	33.3
196h		371 ± 15	368 ± 6.3	68931 ± 3476	1.0	186
196i	p-NO₂-β-phenethyl	601 ± 28	-	-	-	-
196j	p-Cl-β-phenethyl	271 ± 12	-	-	-	-
196k	p-NH₂-β-phenethyl	72 ± 7	-	-	-	-
196l	p-NCS-β-phenethyl	196 ± 14	-	-	-	-
196m	p-azido-β-phenethyl	227 ± 19	-	-	-	-
196n	(p-NHCOCH₂Br)β-phenethyl	61 ± 6	-	-	-	-
196o	(p-NHCO(CH₂)₂CO₂Et)β-phenethyl	86 ± 4	-	-	-	-
197a	NH₂	753 ± 41.3	13725 ± 1256	3981 ± 229	18.2	5.3
197b	-NMe₂	127 ± 6.36	143713 ± 8854	7329 ± 158	1131	57.7
197c	-N(OMe)Me	60 ± 6.4	28162 ± 2565	3935 ± 266	469	65.6
197d	-NHMe	2424 ± 118	44798 ± 2105	4213 ± 206	18.5	1.7
197e (Benzoylecgonine)	-OH	195000	-	-	-	-
197f	HOCH₂-	561 ± 149	-	-	-	-
197g (Tropacocaine)	H	5180 ± 1160	-	-	-	-

Compounds 196e-h possess greater SERT affinity than cocaine, but possess weaker NET/DAT affinities (with the exception of 196g at NET). Compounds 196k, 196n, 196o, and 197c all possess greater DAT affinity than cocaine. Compound 197b (dimethyl amide) displayed a 1,131-fold increased selectivity in affinity over the serotonin transporter, with only slight reductions in potency for the dopamine & norepinephrine transporters. Whereas 197c (Weinreb amide, N-methoxy-N-methyl amide) had a 469× increase at SERT, with greater affinity for DAT than cocaine and an equal NET affinity. 197b was 137×, and 196c 27× less potent at binding to the serotonin transporter, but both had a NET / DAT ratio that made for a better dopaminergic than cocaine. The consideration that large, bulky C2 substituents would alter the spatial conformation of the tropane ring system by distorting the piperidine portion of the system and thus hamper binding appears to be unfounded.

Benzoylecgonine (197e) is the inactive primary metabolite of cocaine generated through hydrolysis of the C2 methyl ester. In vitro binding studies indicate that benzoylecgonine is ~2,200x less potent than cocaine at the dopamine transporter, possibly due to zwitterion formation preventing strong DAT binding. In contrast to in vitro studies, the lack of activity observed in in vivo studies is likely the result of reduced blood–brain barrier penetration than formation of a zwitterion.

Bioisostere 2-position carbmethoxy-ester functional replacements

2β-isoxazole and isoxazoline ring containing analogues
^{IC₅₀ nM values}! Structure! S. Singh's
alphanumeric
assignation
(name)! R! [<sup>3</sup>H]Mazindol! [<sup>3</sup>H]DA! SelectivityUptake/Binding
(Cocaine)	(H)	580 ± 70	570 ± 180	1.0

198a	H	520 ± 40	260 ± 70	0.5
198b	CO₂Et (5′-carboethoxy-)	120 ± 10	290 ± 40	2.4
198c		2230 ± 220	1820 ± 810	0.8
198d	Ph	2000 ± 640	2920 ± 1620	1.5
198e	CH=CHCO₂Me	3600 ± 400	3590 ± 1180	1.0

199a	β(or R)CO₂Et	710 ± 150	1060 ± 340	1.5
199b	α(or S)CO₂Et	5830 ± 630	8460 ± 620	1.4
200		880 ± 350	400 ± 140	0.4

Vinylogous 2β-position carbmethoxy-ester functional replacements

vinylogous 2β analogues
^{Data-set congruent to, and aggregate with, preceding table
IC₅₀ nM values}! Structure! S. Singh's
alphanumeric
assignation! R! [<sup>3</sup>H]Mazindol! [<sup>3</sup>H]DA! SelectivityUptake/Binding

Cocaine		580 ± 70	570 ± 180	1
201a	H	1730 ± 550	1120 ± 390	0.6
201b	Cl	222 ± 49	368 ± 190	1.6
201c	CO₂Et	50 ± 10	130 ± 10	2.6
201d	CH=CHCO₂Et	1220 ± 100	870 ± 50	0.7
201e	PO(OEt)₂	4850 ± 470	5500 ± 70	1.1

Compounds 201b & 201c were significantly more potent than cocaine while compounds 201a, 201d & 201e were significantly less potent. This finding indicates that the presence of a hydrogen bond acceptor (i.e. carbomethoxy) at the 2β position is not absolutely necessary for the creation of high affinity cocaine analogues.

N-modifications

Nitrogen Substitutions
Mazindol comparison table
(^ɑβ-CFT comparison notation)! Compound! S. Singh's
alphanumeric
assignation
(name)! N8-R! [<sup>3</sup>H]Mazindol
binding! [<sup>3</sup>H]DA
uptake! SelectivityUptake/Binding
217 (Cocaine methiodide)	-	10700 ± 1530^ɑ	-	-
(Cocaine)	CH₃	280 ± 60 102^ɑ	320 ± 10	1.1
218 (Norcocaine)	H	303 ± 59^ɑ	-	-
219a		668 ± 67^ɑ	-	-
219b		3370 ± 1080^ɑ	-	-
219c	CH₂CH₂OH	700 ± 100	1600 ± 200	2.3
219d	CH₂CO₂CH₃	480 ± 40	1600 ± 100	3.3
219e	CH₂CO₂H	380 ± 20	2100 ± 400	5.5
220a	SO₂CH₃ (Ms)	1290 ± 80	1970 ± 70	1.5
220b	SO₂CF₃ (Tf)	330 ± 30	760 ± 20	2.3
220c	SO₂NCO	120 ± 10	160 ± 10	1.3
220d	SO₂Ph	20800 ± 3500	61000	2.9
220e	SO₂C₆H₄-4-NO₂ (nosyl)	5720 ± 1140	18800 ± 90	3.3
220f	SO₂C₆H₄-4-OCH₃	6820 ± 580	16400 ± 1400	2.4
221a	NO	99500 ± 12300	231700 ± 39500	2.3
221b	NO₂	7500 ± 900	21200 ± 600	2.8
221c	NHCOCH₃	>1000000	>1000000	-
221d	NH₂	-	-	-

^ɑIC₅₀ (nM) for displacement of [3H]WIN 35428

Tricyclic cocaine analogues

8 to 2 tethered analogues

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes *K_i* (nM) !Compound
(*S. Singh's #*) !Structure![<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	375 ± 68	423 ± 147	155 ± 40	83.3 ± 1.5	0.4
(–)-128	54.3 ± 10.2	60.3 ± 0.4	1.76 ± 0.23	5.24 ± 0.07	0.03
(+)-128	79 ± 19	114 ± 28	1.48 ± 0.07	4.62 ± 0.31	0.01
(±)-128	61.7 ± 8.5	60.3 ± 0.4	2.32 ± 0.23	2.69 ± 0.12	0.04
129	6.86 ± 0.43	24.0 ± 1.3	1.77 ± 0.04	1.06 ± 0.03	0.07
130a	17.2 ± 1.13	10.2 ± 1.4	78.9 ± 0.9	15.0 ± 0.4	7.8
131a	4.00 ± 0.07	2.23 ± 0.12	14.0 ± 0.6	2.99 ± 0.17	6.3
131b	3.61 ± 0.43	11.3 ± 1.1	25.7 ± 4.3	4.43 ± 0.01	2.3
132a	13.7 ± 0.8	14.2 ± 0.1	618 ± 87	3.84 ± 0.35	43.5
133a	149 ± 6	149 ± 2	810 ± 80	51.7 ± 12	5.4

See N-front & back bridged phenyltropanes.

Derivations upon fusions of the tropane's nitrogen bridge! Compound! S. Singh's
alphanumeric
assignation! [<sup>3</sup>H]Mazindol! [<sup>3</sup>H]DA! SelectivityUptake/Binding
	222	44900 ± 6200	115000 ± 15700	2.6

Back-bridged cocaine analogues are considered more akin to untethered cocaine analogs & phenyltropane derivatives (where the nitrogen lone pair is not fixed or constrained) and better mimics their affinities. This is due to when the eighth carbon tropane position is freely rotatable and unbound it preferably occupies the axial position as defining its least energy & most unhindered state. In front-bridged analogs the nitrogen lone pairings rigid fixity makes it reside in an equatorial placing for the piperidine ring-part of the tropane nucleus, pointing to the two-carbon & three methylene unit bridgehead; giving the attested front-bridged cocaine analogues preference for SERT over DAT.

8 to 3 tethered analogues

Thiophene tricyclic tropane analogues^[15] ! Structure! Compound ! R! X! [<sup>3</sup>H]DA Uptake ! [<sup>3</sup>H]5-HT Uptake ! [<sup>3</sup>H]NE Uptake ! 5-HT/DA Selectivity! NE/DA Selectivity
Cocaine			259 ± 19.9	155 ± 0.4	108 ± 3.5	0.60	0.42

5a	H	CO₂Me	268 ± 16.6	2046 ± 42	26.4 ± 1.9	7.63	0.10
5b	Me	CO₂Me	403 ± 20	179 ± 38	4.9 ± 0.2	0.44	0.01
5c	I	CO₂Me	368 ± 1.6	29 ± 1.6	5 ± 1.3	0.08	0.01
7	H	CO₂iPr	428 ± 45.7	1150 ± 1.6	52.3 ± 12.0	2.69	0.12
8	H	CH₂OH	~3000	~1000	~300	~0.33	~ 0.1
9	H	CH₂OAc	610 ± 53	1530 ± 150	283 ± 16	2.51	0.46
10	H	CH₂OCOC(CH₃)₃	1020 ± 70	168 ± 53.5	1180 ± 130	0.16	1.16
11	H	CH₂OCOPh	1750 ± 140	1.53 ± 0.19	894 ± 126	0.0009	0.51
12	H	CH₂OCO-2-naphthyl	1678 ± 124	169 ± 16	1234 ± 166	0.10	0.74
13	H	CH₂NHCOCH₃	6140 ± 50	13330 ± 3150	2430 ± 340	2.17	0.39
14	H	CH₂NHCO₂C(CH₃)₃	2300 ± 380	2360 ± 30	1700 ± 60	1.03	0.74

Conformationally constrained tricyclic tropane analogues^[16] ! Structure! Compound ! R! X! [<sup>3</sup>H]DA Uptake ! [<sup>3</sup>H]5-HT Uptake ! [<sup>3</sup>H]NE Uptake ! DA/5-HT Selectivity! NE/DA Selectivity
Cocaine			423 ± 147	155 ± 0.4	108 ± 3.5	2.7	0.26

8a	4-F	CO₂Me	6620 ± 460	335 ± 45	584 ± 163	2.7	0.26
8b	4-Cl	CO₂Me	853 ± 58	34.3 ± 2.9	208 ± 111	24.8	0.24
8c	3-Cl	CO₂Me	7780 ± 1580	53.6 ± 17.2	231 ± 44	145	0.03
8d	4-Br	CO₂Me	495 ± 13	11 ± 3	178 ± 9	45	0.36
8e	4-I	CO₂Me	764 ± 11	21.9 ± 0.3	213 ± 31	34.9	0.28
8f	4-CF₃	CO₂Me	N/T	12.6 ± 0.5	1830 ± 211	N/T	N/T
8g	H	CO₂Me	481 ± 11	1140 ± 70	53 ± 16	0.42	0.11
8h	4-Me	CO₂Me	649 ± 2	15 ± 0.4	146 ± 28	43.3	0.22
8i	4-OCH₃	CO₂Me	3130 ± 160	56 ± 4	187 ± 5	55.9	0.06
8j	4-iPr	CO₂Me	N/T	10.2 ± 0.4	1110 ± 200	N/T	N/T
8k	3,4-Cl₂	CO₂Me	1920 ± 260	20 ± 1	1000 ± 280	96	0.52
8l	2,3-Cl₂	CO₂Me	950 ± 107	354 ± 188	1210 ± 358	2.4	1.42
8m	3,5-Cl₂	CO₂Me	5600 ± 400	437 ± 0.3	4100 ± 500	12.8	0.73
8n	3,4-F₂	CO₂Me	7440 ± 19	101 ± 8.7	394 ± 98	73.7	0.05
8o	4-Br-3-Cl	CO₂Me	5420 ± 940	2.3 ± 0.1	459 ± 80	2360	0.08
8p	3-Cl-4-I	CO₂Me	3140 ± 450	1.8 ± 0.3	272 ± 55	1740	0.09
8q	2-Cl-4-I	CO₂Me	6640 ± 2080	74 ± 12.2	508 ± 21	89.7	0.08
8r	3-Cl-4-Me	CO₂Me	>10000	6.4 ± 1.3	198 ± 10	>1560	<0.02
8s	3,4-Me₂	CO₂Me	N/T	10.1 ± 1.1	659 ± 128	N/T	N/T

8t	1-Naphthyl	CO₂Me	9720 ± 700	121 ± 3	5370 ± 580	80.3	0.55
8u	2-Naphthyl	CO₂Me	735 ± 235	21 ± 9.9	157 ± 13	35	0.21
8v	1-Pyrenyl	CO₂Me	9920 ± 906	860 ± 20.6	N/T	11.5	N/T
8w	9-Phenanthryl	CO₂Me	1640 ± 30	233 ± 44	13000 ± 1300	39.2	0.86

"N/T" = "not tested"

Tropane ring contraction (azabornane) analogues

7-Azabicyclo[2.2.1]heptane Derivatives! Structure! S. Singh's
alphanumeric
assignation
(name)! DAT
[<sup>3</sup>H]WIN 35428
K_i (nM)
	(Cocaine)	89 ± 4.8
	155a	60400 ± 4800
	155b	96500 ± 42
	155c	5620 ± 390
	155d	18900 ± 1700

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

Substitutions upon the 6 & 7 positions of the tropane! Compound! S. Singh's
alphanumeric
assignation
(name)! X! K_i (nM)
[<sup>3</sup>H]Mazindol binding! K_i (nM)
[<sup>3</sup>H]DA uptake! SelectivityUptake/Binding
(Cocaine)		280 ± 60	320 ± 10	1.1
(Pseudococaine)		10400 ± 300	13800 ± 1500	1.3
225a	2β, 6β-OCH₃	98000 ± 12000	68000 ± 5000	0.7
225b	2α, 6β-OCH₃	190000 ± 11000	510000 ± 110000	2.7
225c	2β, 7β-OCH₃	4200 ± 100	6100 ± 200	1.4
225d	2α, 7β-OCH₃	45000 ± 5000	110000 ± 4000	2.4
225e	2α, 7α-OCH₃	54000 ± 3000	200000 ± 70000	3.7

3β-position 2′—(6′) & 2β-substitution combination analogues

4′-Iodococaine-2β-substituted analogues! Compound! S. Singh's
alphanumeric
assignation! 2β-R! C2′-R! IC₅₀ (nM)
(displacement of [<sup>3</sup>H]WIN 35428)

211a	CH₂OH	H	6214 ± 1269
211b	CH₂OCOCH₃	H	2995 ± 223
211c	CONHCH₃	H	>100000
211d	CO₂Et	H	2031 ± 190
211e	CO₂-i-Pr	H	1377 ± 10
211f	CO₂Ph	H	2019 ± 253
211g	CO₂CH₂Ph	H	4602 ± 325
211h	3-phenyl-1,2,4-oxadiazole	H	3459 ± 60
211i	CH=CH₂	H	2165 ± 253
211j	CH₂CH₃	H	2692 ± 486
212	CO₂-i-Pr	HO	663 ± 70 4507 ± 13^ɑ 34838 ± 796^b

^ɑFor displacement of [3H]paroxetine (5-HTT & NET)
^bFor displacement of [3H]nisoxetine (5-HTT & NET)

3β-Carbamoyl analogues

3-position carbamoyl linkage substituting benzoyloxy analogues! Compound! S. Singh's
alphanumeric
assignation
(name)! X! IC₅₀ (nM)
inhibition of [<sup>3</sup>H]Cocaine binding
(Rat Striatal Tissue)! IC₅₀ (nM)
inhibition of [<sup>3</sup>H]DA uptake
(Rat Striatal Tissue)! Selectivity
uptake/binding
(Cocaine)	(H)	70 ± 10	210 ± 70	3.0

223a	H	5600 ± 700	52600 ± 3000	9.4
223b	4-NO₂	1090 ± 250	5700 ± 1200	5.2
223c	4-NH₂	63300 ± 12200	>100000	-
223d	4-N₃	1000 ± 240	1180 ± 360	1.2
223e	4-NCS	260 ± 60	490 ± 80	1.9

223f	3-NO₂	37 ± 10	178 ± 23	4.8
223g	3-NH₂	2070 ± 340	23100 ± 900	11.1
223h	3-N₃	630 ± 150	3900 ± 1590	6.2
223i	3-NCS	960 ± 210	4900 ± 420	5.1

Phenyl 3-position linkage substitutions

See: List of phenyltropanes (Many phenyltropanes are derived from cocaine metabolites, such as methylecgonidine, as precursors. Whereas fully synthetic methods have been devised from the starting material of vinylcarbenoids & pyrroles.)^[17]

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. This may account for PTs increased behavioral stimulation profile over cocaine. Differences in binding potency have also been explained considering solvation effects; cocaine containing 2β,3β-ester groups being calculated as more solvated than the WIN-type compounds (i.e. troparil). Higher pK_ɑs of the tropane nitrogen (8.65 for cocaine, 9.55 for troparil & 11.95 for vinyl analogue 43a), decreased aqueous solvation & decreased conformational flexibility added to increased binding affinity.

Despite the observation of increased stimulation, phenyltropanes lack the local anesthetic sodium channel blocking effect that the benzoyloxy imparts to cocaine. Beside topical affect, this gives cocaine an affinity for binding to sites on the dopamine and serotonin sodium dependent transport areas that are distinct & specific to MAT in contrast to the general sodium channels; creating a separate mechanism of relational affinity to the transporters in addition to its inhibition of the reuptake for those transporters; this is unique to the local anesthetic value in cocaine & analogues with a similar substitute for the benzoyloxy that leaves the sodium channel blockage ability intact. Rendering such compounds as different functionally in their relation to MAT contrasted to phenyltropane analogues which have the local anesthetic bridge removed.^[18] (Requiring some of the sodium ions to be pumped from the axon via Na+/K+-ATPase). In addition, it even has been postulated that a crucial role regarding the electron energy imparted via voltage sensitization (and thus action potential blockage with a molecule capable of intersecting its specific channel, in the case of cocaine a sodium channel, that potentially serves in re-quantifying its charge) upon a receptor binding site may attenuate the mediating influence of the inhibitory regulation that autoreceptors play by their slowing neurotransmitter release when an efflux is created through an instance of agonism by a compound; allowing said efflux to be continued without the body's attempt to maintain homeostasis enacting in as readily responsive a manner to its conformational change.^[19]

3β-Alkylphenyltropane & 3β-Alkenyl analogues

3-position alkylphenyl linkage substituting benzoyloxy analogues! Compound! S. Singh's
alphanumeric
assignation
(name)! n! IC₅₀ (nM)
[<sup>3</sup>H]Cocaine binding! IC₅₀ (nM)
[<sup>3</sup>H]DA uptake! Selectivity
uptake/binding
	(Cocaine)		101 ± 26	209 ± 20	2.1

224a	₁	885 ± 18	1020 ± 52	1.1
224b	₂	9.9 ± 0.33	70.5 ± 1.0	7.1
224c	₃	344 ± 12	2680 ± 190	7.8
	224d		71.6 ± 0.7	138 ± 9	1.9
	224e		2.10 ± 0.04	5.88 ± 0.09	2.8

The compound 224e, the 3β-styrene analogue, had the highest potency in its group. While 224b & 224c showed the most selectivity, with 224b having a ten-fold greater potency for the dopamine transporter than cocaine.

6-Alkyl-3-benzyltropane analogues

Direct 2,3-pyrimidino fused

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues! Compound! S. Singh's
alphanumeric
assignation
(name/WIN number)! R! K_i (nM)
[<sup>3</sup>H]WIN 35428 binding! IC₅₀ (nM)
[<sup>3</sup>H]DA uptake! Selectivityuptake/binding
	Cocaine		32 ± 5 338 ± 221	405 ± 91 405 ± 91	12.6 1.2
	WIN 35065-2		33 ± 17 314 ± 222	373 ± 10	11.3

(−)-229a	H	33 ± 5	161 ± 100	4.9
229a	H	91 ± 10	94 ± 26	1.0
229b	Me	211 ± 23	-	-
229c	Et	307 ± 28	-	-
229d	n-Pr	4180 ± 418	-	-
229e	n-Bu	8580 ± 249	-	-
229f	Bn	3080 ± 277	-	-

(+)-230a	H	60 ± 6	208 ± 63	3.5
230a	H	108 ± 14	457 ± 104	4.2
230b	Me	561 ± 64	-	-
230c	Et	1150 ± 135	-	-
230d	n-Pr	7240 ± 376	-	-
230e	n-Bu	19700 ± 350	-	-
230f	Bn	7590 ± 53	-	-

231b	Me	57 ± 5	107 ± 36	1.9
231c	Et	3110 ± 187	-	-
231d	n-Pr	5850 ± 702	-	-
231f	Bn	1560 ± 63	-	-

232b	Me	294 ± 29	532 ± 136	1.8
232c	Et	6210 ± 435	-	-
232d	n-Pr	57300 ± 3440	-	-
232f	Bn	3080 ± 277	-	-
	241	Bn	4830 ± 434	-	-

2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.^[20]
(Binding values @ biogenic amine transporters (BATs) for rigid and semi-rigid analogs)! Structure! alphanumeric
assignation! R₁! R₂! hDAT
IC₅₀ (nM)! hSERT
IC₅₀ (nM)! hNET
IC₅₀ (nM)

(—)-3a	H	C₆H₅	58,300 (20,200)	6140 (3350)	NA
(+)-3a	H	C₆H₅	48,700 (20,100)	6030 (3400)	NA

(—)-3b	H	NH₂	NA	NA	NA
(+)-3b	H	NH₂	NA	NA	NA

(—)-3c	H	CH₃	NA	NA	NA
(+)-3c	H	CH₃	NA	NA	NA

(—)-3d	H	H	NA	NA	NA
(+)-3d	H	H	NA	NA	NA
	(+/—)-3e	C₆H₅	C₆H₅	30,000 (11,200)	3650 (1700)	NA

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.^[20]

Piperidine cocaine-homologues

Binding potency of piperidine homologues for displacement of [<sup>3</sup>H]WIN 35428! Compound! S. Singh's
alphanumeric
assignation
(name)! 2β-R! IC₅₀ (nM)
(Cocaine)	CO₂CH₃ (i.e. CO₂Me)	249 ± 37
183a	CO₂CH₃	2522 ± 4
242	H	11589 ± 4
243	CO₂CH₃	8064 ± 4

Cocaine hapten analogues

Structural/Functional intermediate analogues

Piperidine Analogues

Cocaine analogs which elicit noncatalytic antibodies! Compound! S. Singh's
alphanumeric
assignation
(name)! 2β-R
	394 (GNC)^ɑ	CO₂(CH₂)₅CO₂H
	395 (Succinyl Norcocaine)^[21]	CO₂CH₃
	GNE^b^[22] including carrier proteins: GNE-FLiC GNE-KLH GNE-BSA
	396	CONH(CH₂)₅CO₂H

Cocaine transition state analogues (TSAs) which generate catalytic antibodies! Compound! S. Singh's
alphanumeric
assignation
(name)! R

401a	CH₃
401b	(CH₂)₅CO₂H
401c	CH₂CO₂H
401d	COCH₂CH₂CO₂H
401e	H
401f	CH₂CH₂Br
385g	(CH₂)₂NHCO(CH₂)₂CONH₂

402a	O(CH₂)₄NHCO(CH₂)₂CO₂N(CO₂)₂C₆H₄
402b	OH
402c	O(CH₂)₂(p-NH₂C₆H₄)
402d	NH(CH₂)₅CO₂H
402e	O(CH₂)₄NHCO(CH₂)₂CONH₂

403a	NH₂
403b	NHCOCH₂Br
403c	NHCO(CH₂)₃CO₂H
403d	(CH₂)₃NHCO(CH₂)₂CONH₂

A somewhat recent occurrence among tentative modern folklore which has traversed the circling of rumors mostly confined to the likes of universities and popular culture trivia has been that cocaine is one element, or molecule increment of weight or charge etc., away from the molecular structure of sugar.^[30] Though such a statement is false as a general pretense, there is a dextrose based super-structure that has a vaguely similar overlay with cocaine which is "benzoyl-beta-D-glucoside."

Benztropine (3α-Diphenylmethoxy Tropane) Analogues

3α-Diphenylmethoxy tropanes
(Benztropine analog affinities binding to DAT & DA uptake)! Compound! S. Singh's
alphanumeric
assignation
(name)! R! R′! *K_i* (nM)
[<sup>3</sup>H]WIN 35428 binding! IC₅₀ (nM)
[<sup>3</sup>H]DAuptake! Selectivityuptake/binding
	(Cocaine)			388 ± 47	-	-
	(GBR 12909)			11.6 ± 31	-	-

(Benztropine)	H	H	118 ± 9	403 ± 115	3.4
249a	4′-F	H	32.2 ± 10	48	1.5
249b (AHN 1-055)	4′-F	4′-F	11.8 ± 1	71	6.0
249c	3′,4′-di-F	H	27.9 ± 11	181 ± 45.7	6.5
249d	4′-Cl	H	30.0 ± 12	115	3.8
249e	4′-Cl	4′-Cl	20.0 ± 14	75	3.8
249f	3′,4′-di-Cl	H	21.1 ± 19	47	2.2
249g	3′,4′-di-Cl	F	18.9 ± 14	24	1.3
249h	4′-Br	H	37.9 ± 7	29	0.8
249i	4′-Br	4′-Br	91.6	34	0.4
249j	4′-NO₂	H	197 ± 8	219	1.1
249k	4′-CN	H	196 ± 9	222	1.1
249l	4′-CF₃	H	635 ± 10	2155	3.4
249m	4′-OH	H	297 ± 13	677	2.3
249n	4′-OMe	H	78.4 ± 8	468	6.0
249o	4′-OMe	4′-OMe	2000 ± 7	2876	1.4
249p	4′-Me	H	187 ± 5	512	2.7
249q	4′-Me	4′-Me	420 ± 7	2536	6.0
249r	4′-Et	H	520 ± 8	984	1.9
249s	4′-t-Bu	H	1918	4456	2.3
250a	3′-F	H	68.5 ± 12	250 ± 64.7	3.6
250b	3′-F	3′-F	47.4 ± 1	407 ± 63.9	8.6
250c	3′-Cl	H	21.6 ± 7	228 ± 77.1	10.5
250d	3′-CF₃	H	187 ± 5	457 ± 72.0	2.4
251a	2′-F	H	50.0 ± 12	140 ± 17.2	2.8
251b	2′-Cl	H	228 ± 9	997 ± 109	4.4
251c	2′-Me	H	309 ± 6	1200 ± 1.64	3.9
251d	2′-NH₂	H	840 ± 8	373 ± 117	0.4

3α-Diphenylmethoxy-2β-carbomethoxybenztropine
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)! Compound! S. Singh's
alphanumeric
assignation
(name)! R! R′! IC₅₀ (nM)
DAT
(Binding of [<sup>3</sup>H]WIN 35428)! IC₅₀ (nM)
5-HTT
(Binding of [<sup>3</sup>H]Citalopram)! Selectivity
5-HTT/DAT
	(benztropine)			312 ± 1.1	24100 ± 14800	77.2
	(WIN 35428)			12.9 ± 1.1	160 ± 20	12.4
	R-256			2040 ± 283	1460 ± 255	0.7

S-257a	H	H	33.5 ± 4.5	10100 ± 1740	301
S-257b	H	F	13.2 ± 1.9	4930 ± 1200	373
S-257c (difluoropine)	F	F	10.9 ± 1.2	3530 ± 1480	324
S-257d	H	Cl	15.8 ± 0.95	5960 ± 467	377
S-257e	Cl	Cl	91.4 ± 0.85	3360 ± 1480	36.8
S-257f	H	Br	24.0 ± 4.6	5770 ± 493	240
S-257g	Br	Br	72.0 ± 3.65	2430 ± 339	33.7
S-257h	H	I	55.9 ± 10.3	9280 ± 1640	166
S-257i	Br	I	389 ± 29.4	4930 ± 82	12.7
S-257j	I	I	909 ± 79	8550 ± 442	9.4
S-257k	H	Me	49.5 ± 6.0	13200	266
S-257l	Me	Me	240 ± 18.4	9800 ± 2680	40.8

N-Modified 2-carbomethoxybenztropines
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)! Compound! S. Singh's
alphanumeric
assignation
(name)! R! n! IC₅₀ (nM)
DAT
(Binding of [<sup>3</sup>H]WIN 35428)! IC₅₀ (nM)
5-HTT
(Binding of [<sup>3</sup>H]Citalopram)! Selectivity
5-HTT/DAT

258a			20.3 ± 3.5	-	-
258b	H	₁	223 ± 53	4970 ± 700	22.3
258c	H	₃	22.0 ± 11.9	19.7 ± 3	0.9
258d	Br	₃	80.2 ± 8.8	234 ± 0.5	2.9
258e	I	₃	119 ± 11	2200 ± 1250	18.5
258f	H	₅	99.0 ± 28	550 ± 63	5.5
	259			616 ± 88	55200 ± 20000	89.3

N-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes
(Benztropine affinities to DAT & 5-HTT)! Compound! S. Singh's
alphanumeric
assignation
(name)! R! *K_i* (nM)
DAT
(Binding of [<sup>3</sup>H]WIN 35428)! IC₅₀ (nM)
5-HTT
(Uptake of [<sup>3</sup>H]DA)! Selectivity
uptake/binding

260 (AHN 2-003)	H	11.2 ± 11	9.7	0.9
261a	3-phenylpropyl	41.9 ± 11	230	5.5
261b	indole-3-ethyl	44.6 ± 11	1200	26.9
261c	4-phenylbutyl	8.51 ± 14	39	4.6
261d	4-(4′-nitrophenyl)butyl	20.2 ± 11	650	32.2
261e	3-(4′-fluorophenyl)propyl	60.7 ± 12	-	-
262a	n-butyl	24.6 ± 8	370	15.0
262b	cyclopropylmethyl	32.4 ± 9	180	5.5
262c	allyl	29.9 ± 10	14	0.5
262d	benzyl	82.2 ± 15	290	3.5
262e	4-fluorobenzyl	95.6 ± 10	200	2.1
262f	cinnanyl	86.4 ± 12	180	2.1
262g	[bis(4-fluorophenyl)methoxy]ethyl	634 ± 23	-	-
262h	[(4-nitrophenyl)phenylmethoxy]ethyl	57.0 ± 17	-	-
263	acetyl	2340	4600	2.0
264	formyl	2020 ± 13	5400	2.7
265a	tosyl	0%^ɑ	-	-
265b	mesyl	18%^ɑ	-	-
(AHN 2-005)^[31]	CH₂CH=CH₂	-	-	-
(JHW 007)	CH₂CH₂CH₂CH₃	-	-	-
(GA 2-99)	CH₂CH₂NH₂	-	-	-
(GA 103)	CH₂CH₂CH₂CH₂Ph	-	-	-
	266		108 ± 12	130	1.2

8-Oxa-2-carbomethoxy norbenztropines
(8-Oxanortropane benztropine analog affinities to DAT & 5-HTT)! Compound! S. Singh's
alphanumeric
assignation
(name)!! IC₅₀ (nM)
DAT
(Binding of [<sup>3</sup>H]WIN 35428)! IC₅₀ (nM)
5-HTT
(Binding of [<sup>3</sup>H]Citalopram)
R/S-268	2β,3β	>10000	>1660
R/S-269	2α,3β	20300	>1660
R/S-270	2α,3α	22300	>1660
R/S-271	2β,3α	520	>1660

The binding of benztropine analogues to the DAT differs significantly from that of cocaine and the phenyltropanes. Benztropines are considered to be "atypical" DAT ligands because they stabilize the DAT in an inward-facing (closed-to-out) conformation, whereas cocaine and the phenyltropanes stabilize the DAT in an outward-facing (open-to-out) conformation. This difference in DAT binding may be responsible for the lack of cocaine-like behavioral effects observed in animal and human studies of the benztropine analogues and other “atypical” DAT inhibitors. ^[33] Studies of the structure-activity relationships of benztropine have shown that DAT affinity and selectivity over other monoamine transporters is enhanced by 4′,4′-difluorination. Modification of the tropane n-substituent was found to mitigate the anticholinergic effects of benztropine analogues by reducing M1 affinity.^[34] ^[35]

Tropanyl Isoxazoline Analogues

Compound 7a (3′-methoxy-8-methyl-spiro(8-azabicyclo(3.2.1)octane-3,5′(4′H)-isoxazole) allosterically enhances SERT binding of other reuptake ligands. Compound 7a construed as a potentiating allosteric effect (by unveiling occluded configured serotonin uptake-area ligand-site on surface of transporter that allows for binding by exogenous ligand, when SERT is otherwise conformed in a transitional manner where a SERT ligand cannot bind, this effect with compound in question occurs) at concentrations of 10μM—30μM (wherein it acts by interconverting the conformational state of unexposed SERTs to ones exposing the SSRI binding site via a shift to the equilibrium of the MAT) while exerting an inhibitory orthosteric effect when concentrations reach >30μM and above.

7a is the only known compound to allosterically modulate SERT in such a way within in vitro conditions (tianeptine has been shown to do similar, but has only shown efficacy doing so in living in vivo tissue samples). Considering its noncompetitive inhibition of 5-HT transporters decreasing V_max with small change in the Km for serotonin, putatively stabilizing the cytoplasm-facing conformation of SERT: in such respect it is considered to have the opposite effect profile of the anti-addiction drug ibogaine (save for the function by which its anti-addictive properties are thought to be mediated, i.e. α₃β₄ nicotinic channel blockage. cf. 18-Methoxycornaridine for such nicotinergic activity without the likewise SERT affinity).^[37]

Compound 11a possesses similar effects, but acts on the DAT. Similarly, such peripheral DAT considerations (when, as often is, considered conformational rather than otherwise explained as being electrostatic) may constitute the difference in affinity, through allosertic occulsion, between cyclopentyl-ruthenium phenyltropane in its difference from the tricarbonyl-chromium

Dihydroimidazoles

Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for e.g. Beagles) tetracyclic dopamine reuptake inhibitor (of somewhat spurious classification in the former).

It is a loosely functional analog used in cocaine research; due in large part to N-Ethylmaleimide being able to inhibit approximately 95% of the specific binding of [3H]Mazindol to the residues of the MAT binding site(s), however said effect of 10 mM N-Ethylmaleimide was prevented in its entirety by just 10 μM cocaine. Whereas neither 300 μM dopamine or D-amphetamine afforded sufficient protection to contrast the efficacy of cocaine.

Local anesthetics (not usually CNS stimulants)

In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,^[38] although not normally ones that are easily available. These are expected to be more cardiotoxic than phenyltropanes. For example, dimethocaine has behavioral stimulant effects (and therefore not here listed below) if a dose of it is taken that is 10 times the amount of cocaine. Dimethocaine is equipotent to cocaine in terms of its anesthetic equivalency.^[38] Intralipid "rescue" has been shown to reverse the cardiotoxic effects of sodium channel blockers and presumably those effects when from cocaine administered intravenously as well.

Name	Other common names
	Stovaine
	Astracaine, Carticaine, Septanest, Septocaine, Ultracaine, Zorcaine
	Anbesol, Lanacane, Orajel
	Marcaine, Sensorcaine, Vivacaine
	Butyn
	Nesacaine
	Cincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
	Surfacaine, Topocaine
	Duranest
	α-eucaine, β-eucaine
Fomocaine^[39]
Fotocaine
	Cyclaine, Osmocaine
	Chirocaine
	Xylocaine, Betacaine
	Carbocaine, Polocaine
	Epirocain
	Primacaine
	Holocaine
	Metycaine
	Pramoxine
	Citanest
	Pravocaine, Ranocaine, Blockain
	Borocaine (Procaine Borate), Ethocaine
	Alcaine
	Dimethisoquin
	Propaesin, Propazyl, Propylcain
	Naropin
	Pontocaine, Dicaine
	Mesdicain, Mesocain, Mesokain