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:

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

StructureStereoisomerS. 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)
102methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-pseudococaine
(Delcaine, Depsococaine, Dextrocaine, Isococaine, Psicaine.[1])
17215800methyl(1R,2S,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-allococaine1736160methyl(1R,2R,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-allopseudococaine17428500methyl(1R,2S,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
S-cocaine17515800methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-pseudococaine17622500methyl(1S,3R,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allococaine1779820methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allopseudococaine17867700methyl(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
CocaineH249 ± 37615 ± 1202500 ± 702.510.0
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 ± 41052 ± 2318458 ± 10730.47.3
183b 486 ± 63- - - -
183c 144 ± 2- - - -
183d 158 ± 83104 ± 148601 ± 1119.63.8
(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)H249 ± 37615 ± 1202500 ± 702.510.0
184a I 325ɑ- - - -
184b OH 1183 ± 115793 ± 333760 ± 5890.73.2
191 - - - - -
(m-Isococ) - - - - -

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
CocaineH249 ± 37615 ± 1202500 ± 702.510.0
185a I 350ɑ- - - -
185b F 604 ± 671770 ± 3091392 ± 1732.92.3
185c
(2′-Acetoxycocaine)[4]
OAc 70 ± 1219 ± 2072 ± 93.11.0
185d
(2′-Hydroxycocaine)[5]
OH 25 ± 4143 ± 2148 ± 25.71.9
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 ± 19195 ± 101021 ± 750.94.7
(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


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


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]
Ki values for uptake inhibition obtained on HEK-293 heterologously expressed human monoamine transporter cells.
[10] ! Structure! Trivial name! R
(C1 moiety)! Ki (nM) @ DAT! Ki (nM) @ SERT! Ki (nM) @ NET! σ1 affinity
Ki! σ2 affinity
Ki! IC50 (μM) Na+ inhibition
(Vertridine-Stimulated
influx of sodium channels
in Neocortical neurons)c! LogP
(XLogP3 algorithm, Cheng et al., 2007)
(—)-Cocaine H 326 ± 106513 ± 143358 ± 696.7 ± 0.3 μMd[11] "significant"[12] 6.99 ± 2.432.30
(—)-1-methyl-cocaineMe 163 ± 23435 ± 77488 ± 101"unappreciable"1.13 μM16.01 ± 1.902.67
(—)-1-ethyl-cocaineEt 95.1 ± 17.0ɑ1,106 ± 112598 ± 1793.20
(—)-1-n-propyl-cocainen-Pr 871 ± 205ɑ2,949 ± 462b796 ± 1953.56
(—)-1-n-pentyl-cocainen-C5H11 1,272 ± 199b1,866 ± 400ɑ1,596 ± 21b4.64
(—)-1-phenyl-cocainePh 32.3 ± 5.7b974 ± 3081,980 ± 99b524 nM198 nM0.29 ± 0.073.77

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 ± 4.81045 ± 893298 ± 29311.737.0
196a
(Cocaethylene)
195 ± 455801 ± 49310000 ± 75129.751.3
196b n-Pr 196 ± 464517 ± 4306124 ± 26223.331.2
196c i-Pr 219 ± 4825224 ± 149830384 ± 1685115139
196d Ph 112 ± 3133666 ± 333031024 ± 1909300277
196e Bn257 ± 14302 ± 2320794 ± 9501.280.9
196f β-phenethyl 181 ± 10615 ± 5219944 ± 10263.4110
196g γ-phenylpropyl 147 ± 19374 ± 154893 ± 3442.533.3
196h 371 ± 15368 ± 6.368931 ± 34761.0186
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-phenethyl196 ± 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 ± 41.313725 ± 12563981 ± 22918.25.3
197b -NMe2 127 ± 6.36143713 ± 88547329 ± 158113157.7
197c -N(OMe)Me 60 ± 6.428162 ± 25653935 ± 26646965.6
197d -NHMe 2424 ± 11844798 ± 21054213 ± 20618.51.7
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 ± 70570 ± 1801.0
198a H 520 ± 40260 ± 700.5
198b CO2Et (5′-carboethoxy-)120 ± 10290 ± 402.4
198c 2230 ± 2201820 ± 8100.8
198d Ph 2000 ± 6402920 ± 16201.5
198e CH=CHCO2Me 3600 ± 4003590 ± 11801.0
199a β(or R)CO2Et 710 ± 1501060 ± 3401.5
199b α(or S)CO2Et 5830 ± 6308460 ± 6201.4
200 880 ± 350400 ± 1400.4

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 ± 70570 ± 180 1
201a H 1730 ± 5501120 ± 3900.6
201b Cl 222 ± 49368 ± 1901.6
201c CO2Et 50 ± 10130 ± 102.6
201d CH=CHCO2Et 1220 ± 100870 ± 500.7
201e PO(OEt)2 4850 ± 4705500 ± 701.1
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 ± 1530ɑ- -
(Cocaine) CH3 280 ± 60
102ɑ
320 ± 101.1
218
(Norcocaine)
H 303 ± 59ɑ- -
219a 668 ± 67ɑ- -
219b 3370 ± 1080ɑ- -
219c CH2CH2OH 700 ± 1001600 ± 2002.3
219d CH2CO2CH3 480 ± 401600 ± 1003.3
219e CH2CO2H 380 ± 202100 ± 4005.5
220a SO2CH3 (Ms) 1290 ± 801970 ± 701.5
220b SO2CF3 (Tf) 330 ± 30760 ± 202.3
220c SO2NCO 120 ± 10160 ± 101.3
220d SO2Ph 20800 ± 350061000 2.9
220e SO2C6H4-4-NO2 (nosyl) 5720 ± 114018800 ± 903.3
220f SO2C6H4-4-OCH3 6820 ± 58016400 ± 14002.4
221a NO 99500 ± 12300231700 ± 395002.3
221b NO2 7500 ± 90021200 ± 6002.8
221c NHCOCH3 >1000000 >1000000 -
221d NH2 - - -

Tricyclic cocaine analogues

8 to 2 tethered analogues

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes Ki (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
cocaine375 ± 68423 ± 147155 ± 4083.3 ± 1.50.4
(–)-12854.3 ± 10.260.3 ± 0.41.76 ± 0.235.24 ± 0.070.03
(+)-12879 ± 19114 ± 281.48 ± 0.074.62 ± 0.310.01
(±)-12861.7 ± 8.560.3 ± 0.42.32 ± 0.232.69 ± 0.120.04
1296.86 ± 0.4324.0 ± 1.31.77 ± 0.041.06 ± 0.030.07
130a17.2 ± 1.1310.2 ± 1.478.9 ± 0.915.0 ± 0.47.8
131a4.00 ± 0.072.23 ± 0.1214.0 ± 0.62.99 ± 0.176.3
131b3.61 ± 0.4311.3 ± 1.125.7 ± 4.34.43 ± 0.012.3
132a13.7 ± 0.814.2 ± 0.1618 ± 873.84 ± 0.3543.5
133a149 ± 6149 ± 2810 ± 8051.7 ± 125.4
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 ± 6200115000 ± 157002.6
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)31020 ± 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 CO2Me481 ± 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

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
Ki (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! Ki (nM)
[<sup>3</sup>H]Mazindol binding! Ki (nM)
[<sup>3</sup>H]DA uptake! SelectivityUptake/Binding
(Cocaine) 280 ± 60320 ± 101.1
(Pseudococaine) 10400 ± 30013800 ± 15001.3
225a 2β, 6β-OCH3 98000 ± 1200068000 ± 50000.7
225b 2α, 6β-OCH3 190000 ± 11000510000 ± 1100002.7
225c 2β, 7β-OCH3 4200 ± 1006100 ± 2001.4
225d 2α, 7β-OCH3 45000 ± 5000110000 ± 40002.4
225e 2α, 7α-OCH3 54000 ± 3000200000 ± 700003.7

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 ± 13ɑ
34838 ± 796b

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 ± 10210 ± 703.0
223a H 5600 ± 70052600 ± 30009.4
223b 4-NO2 1090 ± 2505700 ± 12005.2
223c 4-NH2 63300 ± 12200>100000 -
223d 4-N3 1000 ± 2401180 ± 3601.2
223e 4-NCS 260 ± 60490 ± 801.9
223f 3-NO2 37 ± 10178 ± 234.8
223g 3-NH2 2070 ± 34023100 ± 90011.1
223h 3-N3 630 ± 1503900 ± 15906.2
223i 3-NCS 960 ± 2104900 ± 4205.1

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 pKɑs 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 ± 26209 ± 202.1
224a 1 885 ± 181020 ± 521.1
224b 2 9.9 ± 0.3370.5 ± 1.07.1
224c 3 344 ± 122680 ± 1907.8
224d 71.6 ± 0.7138 ± 91.9
224e 2.10 ± 0.045.88 ± 0.092.8

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

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues! Compound! S. Singh's
alphanumeric
assignation
(name/WIN number)! R! Ki (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 ± 1011.3
(−)-229a H 33 ± 5161 ± 1004.9
229a H 91 ± 1094 ± 261.0
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 ± 6208 ± 633.5
230a H 108 ± 14457 ± 1044.2
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 ± 5107 ± 361.9
231c Et 3110 ± 187- -
231d n-Pr 5850 ± 702- -
231f Bn 1560 ± 63- -
232b Me 294 ± 29532 ± 1361.8
232c Et 6210 ± 435- -
232d n-Pr 57300 ± 3440- -
232f Bn 3080 ± 277- -
241 Bn 4830 ± 434- -
N.B. The benzylidene derivatives serve as synthetic intermediates for 6-Alkyl-3-benzyltropanes and have not been assayed for biological activity. Compounds 237a and 238a are the same compound as both are the parent for either series with a hydrogen saturated in their respective substitution place.

Direct 2,3-pyrimidino fused

cf. strobamine (at right) for a more efficacious compound as like the below.

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 NANANA
(+)-3c H CH3 NANANA
(—)-3d H H NANANA
(+)-3d H H NANANA
(+/—)-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 CO2CH32522 ± 4
242 H 11589 ± 4
243 CO2CH3 8064 ± 4
cf. phenyltropane piperidine-homologues for compounds with a more optimized conformation that yield higher affinities when binding to MAT.

Cocaine hapten 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
GNEb[22]
including carrier proteins:
GNE-FLiC
GNE-KLH
GNE-BSA
396CONH(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
Cocaine haptens that create catalytic anti-bodies require transitional states as affected in vivo. Monoclonal antibodies generated against BSA-coupled 402e accelerated the rate of cocaine hydrolysis by ~23,000x and eliminated the reinforcing effects of cocaine administration in rats.[23] [24] [25] [26]

Structural/Functional intermediate analogues

Piperidine Analogues

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′! Ki (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 ± 9403 ± 1153.4
249a 4′-F H 32.2 ± 1048 1.5
249b
(AHN 1-055)
4′-F 4′-F 11.8 ± 171 6.0
249c 3′,4′-di-F H 27.9 ± 11181 ± 45.76.5
249d 4′-Cl H 30.0 ± 12115 3.8
249e 4′-Cl 4′-Cl 20.0 ± 1475 3.8
249f 3′,4′-di-Cl H 21.1 ± 1947 2.2
249g 3′,4′-di-Cl F 18.9 ± 1424 1.3
249h 4′-Br H 37.9 ± 729 0.8
249i 4′-Br 4′-Br 91.6 34 0.4
249j 4′-NO2 H 197 ± 8219 1.1
249k 4′-CN H 196 ± 9222 1.1
249l 4′-CF3 H 635 ± 102155 3.4
249m 4′-OH H 297 ± 13677 2.3
249n 4′-OMe H 78.4 ± 8468 6.0
249o 4′-OMe 4′-OMe 2000 ± 72876 1.4
249p 4′-Me H 187 ± 5512 2.7
249q 4′-Me 4′-Me 420 ± 72536 6.0
249r 4′-Et H 520 ± 8984 1.9
249s 4′-t-Bu H 1918 4456 2.3
250a 3′-F H 68.5 ± 12250 ± 64.73.6
250b 3′-F 3′-F 47.4 ± 1407 ± 63.98.6
250c 3′-Cl H 21.6 ± 7228 ± 77.110.5
250d 3′-CF3 H 187 ± 5457 ± 72.02.4
251a 2′-F H 50.0 ± 12140 ± 17.22.8
251b 2′-Cl H 228 ± 9997 ± 1094.4
251c 2′-Me H 309 ± 61200 ± 1.643.9
251d 2′-NH2 H 840 ± 8373 ± 1170.4
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 ± 1480077.2
(WIN 35428) 12.9 ± 1.1160 ± 2012.4
R-256 2040 ± 2831460 ± 2550.7
S-257a H H 33.5 ± 4.510100 ± 1740301
S-257b H F 13.2 ± 1.94930 ± 1200373
S-257c
(difluoropine)
F F 10.9 ± 1.23530 ± 1480324
S-257d H Cl 15.8 ± 0.955960 ± 467377
S-257e Cl Cl 91.4 ± 0.853360 ± 148036.8
S-257f H Br 24.0 ± 4.65770 ± 493240
S-257g Br Br 72.0 ± 3.652430 ± 33933.7
S-257h H I 55.9 ± 10.39280 ± 1640166
S-257i Br I 389 ± 29.44930 ± 8212.7
S-257j I I 909 ± 798550 ± 4429.4
S-257k H Me 49.5 ± 6.013200 266
S-257l Me Me 240 ± 18.49800 ± 268040.8
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 ± 534970 ± 70022.3
258c H 3 22.0 ± 11.919.7 ± 30.9
258d Br 3 80.2 ± 8.8234 ± 0.52.9
258e I 3 119 ± 112200 ± 125018.5
258f H 5 99.0 ± 28550 ± 635.5
259 616 ± 8855200 ± 2000089.3
N-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes
(Benztropine affinities to DAT & 5-HTT)! Compound! S. Singh's
alphanumeric
assignation
(name)! R! Ki (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 ± 119.7 0.9
261a 3-phenylpropyl 41.9 ± 11230 5.5
261b indole-3-ethyl 44.6 ± 111200 26.9
261c 4-phenylbutyl 8.51 ± 1439 4.6
261d 4-(4′-nitrophenyl)butyl 20.2 ± 11650 32.2
261e 3-(4′-fluorophenyl)propyl 60.7 ± 12- -
262a n-butyl 24.6 ± 8370 15.0
262b cyclopropylmethyl 32.4 ± 9180 5.5
262c allyl 29.9 ± 1014 0.5
262d benzyl 82.2 ± 15290 3.5
262e 4-fluorobenzyl 95.6 ± 10200 2.1
262f cinnanyl 86.4 ± 12180 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 ± 135400 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 ± 12130 1.2
ɑInhibition at 10 μM
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 Vmax 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

See: List of Mazindol analogues

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 [<sup>3</sup>H]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.

List of local anesthetics
NameOther 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

See also

Common analogues to prototypical D-RAs:

External links

Notes and References

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  2. Gatley SJ, Yu DW, Fowler JS, MacGregor RR, Schlyer DJ, Dewey SL, Wolf AP, Martin T, Shea CE, Volkow ND . Studies with differentially labeled [11C]cocaine, [11C]norcocaine, [11C]benzoylecgonine, and [11C]- and 4′-[18F]fluorococaine to probe the extent to which [11C]cocaine metabolites contribute to PET images of the baboon brain . Journal of Neurochemistry . 62 . 3 . 1154–62 . March 1994 . 8113802 . 10.1046/j.1471-4159.1994.62031154.x. 25854431 .
  3. Cocaine Receptor: Biochemical Characterization and Structure-Activity Relationships of Cocaine Analogues at Dopamine Transporter . Carroll, F. I. . Lewin, A. H. . Boja, J. W. . Kuhar, M. J. . Journal of Medicinal Chemistry . 35 . 6 . 1992 . 969–981 . 10.1021/jm00084a001 . 1552510.
  4. 9427328 . 1997 . Seale . TW . Avor . K . Singh . S . Hall . N . Chan . HM . Basmadjian . GP . 2′-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding . 8 . 16 . 3571–5 . NeuroReport . 10.1097/00001756-199711100-00030. 24348794 .
  5. Singh . S . Basmadjian . GP . Avor . K . Pouw . B . Seale . TW . 1997 . A convenient synthesis of 2?- or 4?-hydroxycocaine . Synthetic Communications . 27 . 22. 4003–4012 . 10.1080/00397919708005923 .
    et. el-Moselhy . TF . Avor . KS . Basmadjian . GP . Sep 2001 . 2?-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies . Archiv der Pharmazie . 334 . 8–9. 275–8 . 11688137 . 10.1002/1521-4184(200109)334:8/9<275::aid-ardp275>3.0.co;2-b . 41556606 .
    et. Seale . TW . Avor . K . Singh . S . Hall . N . Chan . HM . Basmadjian . GP . 1997 . 2?-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding . NeuroReport . 8 . 16. 3571–5 . 9427328 . 10.1097/00001756-199711100-00030 . 24348794 .
  6. 1984 . Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine . 6708474 . Journal of Analytical Toxicology . 8 . 1. 29–34 . Smith . RM . Poquette . MA . Smith . PJ . 10.1093/jat/8.1.29.
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  13. http://www.nature.com/npp/journal/v26/n4/full/1395834a.html Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference: Possible Dependence on Dopamine Uptake Blockade
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  20. Appell. Michael. Dunn. William J.. Reith. Maarten E.A.. Miller. Larry. Flippen-Anderson. Judith L.. An Analysis of the Binding of Cocaine Analogues to the Monoamine Transporters Using Tensor Decomposition 3-D QSAR. Bioorganic & Medicinal Chemistry. 10. 5. 2002. 1197–1206. 0968-0896. 10.1016/S0968-0896(01)00389-3. 11886784.
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