List of cocaine analogues

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Template:Short description Script error: No such module "Multiple image". 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:Template:Efn

  • 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.Template:Efn

Analogs sensu stricto

Cocaine Stereoisomers

Template:Table alignment

Structure Stereoisomer Template:Verth IC50 (nM)
[3H]WIN 3542 inhibition to
rat striatal membranes
Mean error standard ≤5% in all cases 		IUPAC
nomenclature
File:R-cocaine.svg R-cocaine
(Erythroxyline) 		102 methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
File:R-pseudococaine.svg 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
File:R-allococaine.svg R-allococaine 173 6160 methyl(1R,2R,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
File:R-allopseudococaine.svg R-allopseudococaine 174 28500 methyl(1R,2S,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
File:S-cocaine.svg S-cocaine 175 15800 methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
File:S-pseudococaine.svg S-pseudococaine 176 22500 methyl(1S,3R,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
File:S-allococaine.svg S-allococaine 177 9820 methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
File:S-allopseudococaine.svg S-allopseudococaine 178 67700 methyl(1S,3S,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
File:Cocaine Pharmacophore.svg
The structure of cocaine with relevant structural motifs for activity at the dopamine transporter highlighted.

While it was originally thought that the 2β-carbomethoxy moiety interacted with the DAT through hydrogen bonding, subsequent research has indicated that electrostatic (ionic) interactions are the primary means of interactions with the DAT.Template:Efn

There are eight stereoisomers of cocaine (excluding mesomers and modifications to the internal portion of the tropane ring).Template:Efn 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)Template:Efn
Data-set congruent to, and aggregate with, following tables
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name) 		4′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Cocaine H 249 ± 37 615 ± 120 2500 ± 70 2.5 10.0
non-benzoyloxy analogue
comparative ligands
Template:Smallsub		 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
Satendra Singh Rev
183a I 2522 ± 4 1052 ± 23 18458 ± 1073 0.4 7.3
183b Ph 486 ± 63 - - - -
183c OAc 144 ± 2 - - - -
183d OH 158 ± 8 3104 ± 148 601 ± 11 19.6 3.8
(4′-Fluorococaine)[2] F - - - - -
(para-Isothiocyanatobenzoylecgonine
methyl ester)[3]
(p-Isococ)		 NCS - - - - -

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.Template:Efn

meta-substituted benzoylmethylecgonines

Carbon 3′-hydrogen Substitutions (benzene-3′ "meta" substituted benzoyloxytropanes)Template:Efn
Data-set congruent to, and aggregate with, preceding and following tables
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name) 		3′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

(cocaine) H 249 ± 37 615 ± 120 2500 ± 70 2.5 10.0
Satendra Singh Rev
184a I 325ɑ - - - -
184b OH 1183 ± 115 793 ± 33 3760 ± 589 0.7 3.2
191 OBn - - - - -
(m-Isococ) NCS - - - - -
  • ɑIC50 value for displacement of [3H]cocaine

ortho-substituted benzoylmethylecgonines

Carbon 2′-hydrogen Substitutions (benzene-2′ "ortho" substituted benzoyloxytropanes)Template:Efn
Data-set congruent to, and aggregate with, preceding and following tables
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name) 		2′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Cocaine H 249 ± 37 615 ± 120 2500 ± 70 2.5 10.0
Satendra Singh Rev
185a I 350ɑ - - - -
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.Template:Efn

Manifold and termination benzoyloxy phenyl-substitutions

Vanillylmethylecgonine 186b
File:Hydroxymethoxycocaine.svg File:Cocaine analog 186.svg

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)Template:Efn
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

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

File:Cocaine analog 186.svg 186 HO H I 215 ± 19 195 ± 10 1021 ± 75 0.9 4.7
File:Hydroxymethoxycocaine.svg (Vanillylmethylecgonine)[6] H OCH3 OH - - - - -
Terminating Phenyl Carbon Ring Fusions & AlterationsTemplate:Efn
Data-set congruent to, and aggregate with, preceding table
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name) 		C=R DAT

[3H]Cocaine (IC50)

File:Cocaine analog 187.svg 187 1-naphthalene 742 ± 48
File:Cocaine analog 188.svg 188 2-naphthalene 327 ± 63

Benzoyl and carbomethoxy branch modifications

Script error: No such module "Multiple image".

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

File:REC structure.png
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

Template:Sort-under

C1 substitutions[9]
Ki values for uptake inhibition obtained on HEK-293 heterologously expressed human monoamine transporter cells.[10]
Structure Trivial name Template:Verth 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 		Template:Verth
(—)-Cocaine H 326 ± 106 513 ± 143 358 ± 69 6.7 ± 0.3 μMd[11] "significant"[12] 6.99 ± 2.43 2.30
File:1-methylcocaine.svg (—)-1-methyl-cocaine Me 163 ± 23 435 ± 77 488 ± 101 "unappreciable" 1.13 μM 16.01 ± 1.90 2.67
File:1-ethylcocaine.svg (—)-1-ethyl-cocaine Et 95.1 ± 17.0ɑ 1,106 ± 112 598 ± 179 — — — 3.20
File:1-propylcocaine.svg (—)-1-n-propyl-cocaine n-Pr 871 ± 205ɑ 2,949 ± 462b 796 ± 195 — — — 3.56
File:1-pentylcocaine.svg (—)-1-n-pentyl-cocaine n-C5H11 1,272 ± 199b 1,866 ± 400ɑ 1,596 ± 21b — — — 4.64
File:1-phenylcocaine.svg (—)-1-phenyl-cocaine Ph 32.3 ± 5.7b 974 ± 308 1,980 ± 99b 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 Ki.[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 SubstitutionsTemplate:Efn
(IC50 nM values)
Structure S. Singh's
alphanumeric
assignation
(name) 		R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Satendra Singh Rev
(Cocaine) Me 89 ± 4.8 1045 ± 89 3298 ± 293 11.7 37.0
196a
(Cocaethylene)		 Et 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 cinnamyl 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 - - - -
Satendra Singh Rev 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 - - - -
Satendra Singh Rev 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.Template:Efn 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.Template:Efn 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.Template:Efn 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 bindingTemplate:Efn appears to be unfounded.Template:Efn

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.Template:Efn

Bioisostere 2-position carbmethoxy-ester functional replacements

2β-isoxazole and isoxazoline ring containing analoguesTemplate:EfnTemplate:EfnTemplate:Efn
IC50 nM values
Structure S. Singh's
alphanumeric
assignation
(name) 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

(Cocaine) (H) 580 ± 70 570 ± 180 1.0
Satendra Singh Rev
198a H 520 ± 40 260 ± 70 0.5
198b CO2Et (5′-carboethoxy-) 120 ± 10 290 ± 40 2.4
198c BOC 2230 ± 220 1820 ± 810 0.8
198d Ph 2000 ± 640 2920 ± 1620 1.5
198e CH=CHCO2Me 3600 ± 400 3590 ± 1180 1.0
File:Singh 199a-b.svg
199a β(or R)CO2Et 710 ± 150 1060 ± 340 1.5
199b α(or S)CO2Et 5830 ± 630 8460 ± 620 1.4
File:Singh 200.svg 200 880 ± 350 400 ± 140 0.4

Vinylogous 2β-position carbmethoxy-ester functional replacements

vinylogous 2β analoguesTemplate:Efn
Data-set congruent to, and aggregate with, preceding table
IC50 nM values
Structure S. Singh's
alphanumeric
assignation 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

File:Cocaine analog 201.svg
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.Template:Efn

N-modifications

Nitrogen Substitutions
Mazindol comparison table
(ɑβ-CFT comparison notation)Template:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		N8-R [3H]Mazindol
binding 		[3H]DA
uptake 		Selectivity

Uptake/Binding

File:Cocaine methiodide.svg 217
(Cocaine methiodide)		 - 10700 ± 1530ɑ - -
Satendra Singh Rev (Cocaine) CH3 280 ± 60
102ɑ		 320 ± 10 1.1
218
(Norcocaine)		 H 303 ± 59ɑ - -
219a Bn 668 ± 67ɑ - -
219b Ac 3370 ± 1080ɑ - -
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 Ki (nM) Template:Efn
Compound
(S. Singh's #) 		Structure [3H]Mazindol binding [3H]DA uptake [3H]5-HT uptake [3H]NE uptake selectivity
[3H]5-HT/[3H]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 File:Singh 128.svg 61.7 ± 8.5 60.3 ± 0.4 2.32 ± 0.23 2.69 ± 0.12 0.04
129 File:Singh 129.svg 6.86 ± 0.43 24.0 ± 1.3 1.77 ± 0.04 1.06 ± 0.03 0.07
130a File:Singh 130a.svg 17.2 ± 1.13 10.2 ± 1.4 78.9 ± 0.9 15.0 ± 0.4 7.8
131a File:Singh 131a.svg 4.00 ± 0.07 2.23 ± 0.12 14.0 ± 0.6 2.99 ± 0.17 6.3
131b File:Singh 131b.svg 3.61 ± 0.43 11.3 ± 1.1 25.7 ± 4.3 4.43 ± 0.01 2.3
132a File:Singh 132a.svg 13.7 ± 0.8 14.2 ± 0.1 618 ± 87 3.84 ± 0.35 43.5
133a File:Singh 133a.svg 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 bridgeTemplate:Efn
Compound S. Singh's
alphanumeric
assignation 		[3H]Mazindol [3H]DA Selectivity

Uptake/Binding

File:Cocaine analog 222.svg 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.Template:Efn

8 to 3 tethered analogues

Thiophene tricyclic tropane analogues[17]
Structure Compound R X [3H]DA Uptake [3H]5-HT Uptake [3H]NE Uptake 5-HT/DA Selectivity NE/DA Selectivity
Cocaine 259 ± 19.9 155 ± 0.4 108 ± 3.5 0.60 0.42
File:Zhang thiophene tropane.svg
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[18]
Structure Compound R X [3H]DA Uptake [3H]5-HT Uptake [3H]NE Uptake DA/5-HT Selectivity NE/DA Selectivity
Cocaine 423 ± 147 155 ± 0.4 108 ± 3.5 2.7 0.26
File:Zhang tricyclic tropane.svg
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
File:Zhang tricyclic tropane 2.svg
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

File:NorbornaneBMEanalog.png
Comparison of tropane ring versus the norbornane in overlay emphasizing the conformational differences of the benzoyl branch between the tropane ring system (dark blue on right) and norbornane ring system (light blue on right).
7-Azabicyclo[2.2.1]heptane DerivativesTemplate:Efn
Structure S. Singh's
alphanumeric
assignation
(name) 		DAT
[3H]WIN 35428
Ki (nM)
(Cocaine) 89 ± 4.8
File:Cocaine analogue 155a.svg 155a 60400 ± 4800
File:Cocaine analogue 155b.svg 155b 96500 ± 42
File:Cocaine analogue 155c.svg 155c 5620 ± 390
File:Cocaine analogue 155d.svg 155d 18900 ± 1700

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

File:Methyl (1R,4R,5S)-4-chloro-8-methyl-3-(phenylsulfanyl)-8-azabicyclo(3.2.1)oct-2-ene-2-carboxylate.svg
Phenylsulfanyl, C2-C3 unsaturated nonisomeric (C2 inclusive) C4 chloro analog.[15]
Substitutions upon the 6 & 7 positions of the tropaneTemplate:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		X Ki (nM)
[3H]Mazindol binding 		Ki (nM)
[3H]DA uptake 		Selectivity

Uptake/Binding

(Cocaine) 280 ± 60 320 ± 10 1.1
(Pseudococaine) 10400 ± 300 13800 ± 1500 1.3
File:Cocaine analog 225a.svg 225a 2β, 6β-OCH3 98000 ± 12000 68000 ± 5000 0.7
File:Cocaine analog 225b.svg 225b 2α, 6β-OCH3 190000 ± 11000 510000 ± 110000 2.7
File:Cocaine analog 225c.svg 225c 2β, 7β-OCH3 4200 ± 100 6100 ± 200 1.4
File:Cocaine analog 225d.svg 225d 2α, 7β-OCH3 45000 ± 5000 110000 ± 4000 2.4
File:Cocaine analog 225e.svg 225e 2α, 7α-OCH3 54000 ± 3000 200000 ± 70000 3.7

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

4′-Iodococaine-2β-substituted analoguesTemplate:Efn
Compound S. Singh's
alphanumeric
assignation 		2β-R C2′-R IC50 (nM)
(displacement of [3H]WIN 35428)
File:Cocaine analog 211.svg
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
File:Cocaine analog 212.svg 212 CO2-i-Pr HO 663 ± 70
4507 ± 13ɑ
34838 ± 796b
  • 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 analoguesTemplate:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		X IC50 (nM)
inhibition of [3H]Cocaine binding
(Rat Striatal Tissue) 		IC50 (nM)
inhibition of [3H]DA uptake
(Rat Striatal Tissue) 		Selectivity
uptake/binding
(Cocaine) (H) 70 ± 10 210 ± 70 3.0
File:Cocaine analog 223a-e.svg
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
File:Cocaine analog 223f-i.svg
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

File:Phenyltropane.gif
A 3-Dimensional (stick-&-ball) rendering of Troparil: A structural analogue of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands; those of the phenyltropane class. (Here it is depicted in an unfavourable conformation of the O-Me; The methyl has to be at the other oxygen and trans to optimize its functional stimulation.)

Script error: No such module "Multiple image".

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.)[19]

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.Template:Efn This may account for PTs increased behavioral stimulation profile over cocaine.Template:Efn 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.Template:Efn

File:WIN 35,065-2.svg File:WF-31.svg File:RTI-11W.svg File:WF-23.svg

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.[20] (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.[21]

Various phenyltropane examples

3β-Alkylphenyltropane & 3β-Alkenyl analogues

3-position alkylphenyl linkage substituting benzoyloxy analoguesTemplate:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		n IC50 (nM)
[3H]Cocaine binding 		IC50 (nM)
[3H]DA uptake 		Selectivity
uptake/binding
(Cocaine) 101 ± 26 209 ± 20 2.1
File:Cocaine analog 224.svg
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.Template:Efn

6-Alkyl-3-benzyltropane analogues

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analoguesTemplate:Efn
Sub-category
(S. Singh compound #) 		a
R=H 		b
R=Me 		c
R=Et 		d
R=n-Pr 		e
R=n-Bu 		f
R=Bn
2β,6α-isomers:
(229a—f)
File:Cocaine analog 229a.svg File:Cocaine analog 229b.svg File:Cocaine analog 229c.svg File:Cocaine analog 229d.svg File:Cocaine analog 229e.svg File:Cocaine analog 229f.svg
2α,6α-isomers:
(230a—f)
File:Cocaine analog 230a.svg File:Cocaine analog 230b.svg File:Cocaine analog 230c.svg File:Cocaine analog 230d.svg File:Cocaine analog 230e.svg File:Cocaine analog 230f.svg
2β,6β-isomers:
(231a—f)
File:Cocaine analog 229a.svg File:Cocaine analog 231b.svg File:Cocaine analog 231c.svg File:Cocaine analog 231d.svg File:Cocaine analog 231e.svg File:Cocaine analog 231f.svg
2α,6β-isomers:
(232a—f)
File:Cocaine analog 230a.svg File:Cocaine analog 232b.svg File:Cocaine analog 232c.svg File:Cocaine analog 232d.svg File:Cocaine analogue 232e.svg File:Cocaine analog 232f.svg
6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analoguesTemplate:Efn
Compound S. Singh's
alphanumeric
assignation
(name/WIN number) 		R Ki (nM)
[3H]WIN 35428 binding 		IC50 (nM)
[3H]DA uptake 		Selectivity

uptake/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
File:229 Analogue Scaffold.svg
(−)-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 - -
File:230 Analogue Scaffold.svg
(+)-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 - -
File:231 Analogue Scaffold.svg
231b Me 57 ± 5 107 ± 36 1.9
231c Et 3110 ± 187 - -
231d n-Pr 5850 ± 702 - -
231f Bn 1560 ± 63 - -
File:232 Analogue Scaffold.svg
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 - -
Benzylidene derivatives of 6-alkyl-3-benzyltropanesTemplate:Efn
Sub-category
(S. Singh compound #) 		a
R=H 		b
R=Me 		c
R=Et 		d
R=n-Pr 		e
R=n-Bu 		f
R=Bn
6α-isomers:
(237a—f)
File:Cocaine analog 237a.svg File:Cocaine analog 237b.svg File:Cocaine analog 237c.svg File:Cocaine analog 237d.svg File:Cocaine analog 237e.svg File:Cocaine analog 237f.svg
6β-isomers (exo):
(238a—f)
File:Cocaine analog 238a.svg File:Cocaine analog 238b.svg File:Cocaine analog 238c.svg File:Cocaine analog 238d.svg File:Cocaine analog 238e.svg

File:Cocaine analog 238f.svg

3β-benzyl derivatives:
(239a—f)
File:Cocaine analog 239a.svg File:Cocaine analog 239b.svg File:Cocaine analog 239c.svg File:Cocaine analog 239d.svg File:Cocaine analog 239e.svg File:Cocaine analog 239f.svg
intermediate
alkylidene esters:
(240a—f)
File:Cocaine analog 240a.svg File:Cocaine analog 240b.svg File:Cocaine analog 240c.svg File:Cocaine analog 240d.svg File:Cocaine analog 240e.svg File:Cocaine analog 240f.svg

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

Script error: No such module "Multiple image".

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

2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.[22]
(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)
File:2,3-fused pyrimidino cocaine analogue 3a.svg
(−)-3a H C6H5 58,300 (20,200) 6140 (3350) Template:NA
(+)-3a H C6H5 48,700 (20,100) 6030 (3400) Template:NA
File:2,3-fused pyrimidino cocaine analogue 3b.svg
(−)-3b H NH2 Template:NA Template:NA Template:NA
(+)-3b H NH2 Template:NA Template:NA Template:NA
File:2,3-fused pyrimidino cocaine analogue 3c.svg
(−)-3c H CH3 Template:NA Template:NA Template:NA
(+)-3c H CH3 Template:NA Template:NA Template:NA
File:2,3-fused pyrimidino cocaine analogue 3d.svg
(−)-3d H H Template:NA Template:NA Template:NA
(+)-3d H H Template:NA Template:NA Template:NA
File:2,3-fused pyrimidino cocaine analogue 3e.svg (+/—)-3e C6H5 C6H5 30,000 (11,200) 3650 (1700) Template:NA
  • "NA" = "no affinity", e.g. unquantifiable.

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.[22]

Piperidine cocaine-homologues

File:Methyl (1R,2R,3S,5S)-8-methyl-3-(tricyclo(9.4.0.0³,⁸)pentadeca-1(11),3,5,7,12,14-hexaene-2-carbonyloxy)-8-azabicyclo(3.2.1)octane-2-carboxylate.svg
Tricyclo benzoyloxy dibenzene cocaine analogue. cf. benztropine compound #277, tropatepine, etc.[15]
Binding potency of piperidine homologues for displacement of [3H]WIN 35428Template:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		2β-R IC50 (nM)
(Cocaine) CO2CH3
(i.e. CO2Me)		 249 ± 37
File:Cocaine analog 183a.svg 183a CO2CH3 2522 ± 4
File:Cocaine analog 242.svg 242 H 11589 ± 4
File:Cocaine analog 243.svg 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

File:Cocaine analog GNC.svg
"GNC", a cocaine analog designed to minimize the formation of noncocaine-like structures through its chemical coupling to the Ad proteins; all while maintaining the element of its antigenic determinant from the moiety of cocaine.[23]
Cocaine analogs which elicit noncatalytic antibodiesTemplate:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		2β-R
File:CocaineNoncatalyticHapten394.svg 394
(GNC)ɑ		 CO2(CH2)5CO2H
File:CocaineNoncatalyticHapten395.svg 395
(Succinyl Norcocaine)[24]		 CO2CH3
File:Cocaine hapten GNE.svg GNEb[25]
including carrier proteins:
GNE-FLiC
GNE-KLH
GNE-BSA
File:CocaineNoncatalyticHapten396.svg 396 CONH(CH2)5CO2H
  • ɑ6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carbonyloxy-hexanoic acid
  • b6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid
File:Cocaine analog 400 intermediate.svg
Tetrahedral-intermediate cocaine-hapten compound #400
Cocaine transition state analogues (TSAs) which generate catalytic antibodiesTemplate:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		R
File:Cocaine analog 401.svg
401a CH3
401b (CH2)5CO2H
401c CH2CO2H
401d COCH2CH2CO2H
401e H
401f CH2CH2Br
385g (CH2)2NHCO(CH2)2CONH2
File:Cocaine analog 402.svg
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
File:Cocaine analog 403.svg
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.[26][27][28][29]

Anti-idiotypic & butyl-cholinesterase mediated immunopharmacotherapy cocaine analogs[30]
K1-KLH/BSA[31] K2-KLH/BSA
File:K1-KLH-BSA.svg File:K2-KLH-BSA.svg

Structural/Functional intermediate analogues

Piperidine Analogues

File:JZ-IV-10 chemical structure.png

File:(+)-CPCA.svg

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.[33] 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."

File:Benzoyl-beta-D-glucoside.svg

Benztropine (3α-Diphenylmethoxy Tropane) Analogues

3α-Diphenylmethoxy tropanes
(Benztropine analog affinities binding to DAT & DA uptake)Template:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		R R′ Ki (nM)
[3H]WIN 35428 binding 		IC50 (nM)
[3H]DA

uptake

Selectivity

uptake/binding

(Cocaine) 388 ± 47 - -
(GBR 12909) 11.6 ± 31 - -
File:Cocaine analog 249-251.svg
(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)Template:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		R R′ IC50 (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Binding of [3H]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
File:Cocaine analog 257.svg
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)Template:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		R n IC50 (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Binding of [3H]Citalopram) 		Selectivity
5-HTT/DAT
File:Cocaine analog 258.svg
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)Template:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		R Ki (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Uptake of [3H]DA) 		Selectivity
uptake/binding
File:Cocaine analog 260-265.svg
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)[34] CH2CH=CH2 - - -
(JHW 007)[34] CH2CH2CH2CH3 - - -
(GA 2-99)[34] CH2CH2NH2 - - -
(GA 103)[34] CH2CH2CH2CH2Ph - - -
File:Cocaine analog 266.svg 266 108 ± 12 130 1.2

ɑInhibition at 10 μM

8-Oxa-2-carbomethoxy norbenztropines
(8-Oxanortropane benztropine analog affinities to DAT & 5-HTT)Template:Efn
Compound S. Singh's
alphanumeric
assignation
(name) 		IC50 (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Binding of [3H]Citalopram)
File:Cocaine analog 268.svg R/S-268 2β,3β >10000 >1660
R/S-269 2α,3β 20300 >1660
R/S-270 2α,3α 22300 >1660
File:Cocaine analog 271.svg 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. [36] 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.[37][38]

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).[40]

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

Alicyclic Amine Analogues

EXP-561 Butyltolylquinuclidine
File:EXPfivesixone.png File:Butyltolylquinuclidine.png

Dihydroimidazoles

File:Mazindol analogs 2.svg
Possible substitutions of the Mazindol molecular structure.

See: List of Mazindol analogues

Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for e.g. BeaglesTemplate:Efn) 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.Template:Efn

Local anesthetics (not usually CNS stimulants)

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In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,[41] 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.[41] 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
Name Other common names
Amylocaine Stovaine
Articaine Astracaine, Carticaine, Septanest, Septocaine, Ultracaine, Zorcaine
Benzocaine Anbesol, Lanacane, Orajel
Bupivacaine Marcaine, Sensorcaine, Vivacaine
Butacaine Butyn
Chloroprocaine Nesacaine
Cinchocaine/Dibucaine Cincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
Cyclomethycaine Surfacaine, Topocaine
Etidocaine Duranest
Eucaine α-eucaine, β-eucaine
Fomocaine[42]
Fotocaine[42]
Hexylcaine Cyclaine, Osmocaine
Levobupivacaine Chirocaine
Lidocaine/Lignocaine Xylocaine, Betacaine
Mepivacaine Carbocaine, Polocaine
Meprylcaine/Oracaine Epirocain
Metabutoxycaine Primacaine
Phenacaine/Holocaine Holocaine
Piperocaine Metycaine
Pramocaine/Pramoxine Pramoxine
Prilocaine Citanest
Propoxycaine/Ravocaine Pravocaine, Ranocaine, Blockain
Procaine/Novocaine Borocaine (Procaine Borate), Ethocaine
Proparacaine/Alcaine Alcaine
Quinisocaine Dimethisoquin
Risocaine Propaesin, Propazyl, Propylcain
Ropivacaine Naropin
Tetracaine/Amethocaine Pontocaine, Dicaine
Trimecaine Mesdicain, Mesocain, Mesokain

See also

File:Cinnamoylcocaine.svg
Methylecgonine cinnamate, an alkaloid widely considered inactive in its own right, but postulated to be active under pyrolysis. (cf. alkylphenyltropane analogue "224e") It is, however, found in patents of active cocaine analogue structures.[43][44]

Common analogues to prototypical D-RAs:

Notes (inclu. specific locations of citations from within references used)

Template:Notelist

References

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    et. Script error: No such module "Citation/CS1".
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  10. ↑ a b c Script error: No such module "Citation/CS1". Full article
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  13. ↑ Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference: Possible Dependence on Dopamine Uptake Blockade Pascal Romieu et al. Neuropsychopharmacology (2002) 26 444-455.10.1038/S0893-133X(01)00391-8
  14. ↑ Script error: No such module "Citation/CS1".Script error: No such module "Unsubst".
  15. ↑ a b c d e U.S. patent 6479509
  16. ↑ Script error: No such module "Citation/CS1".
  17. ↑ Script error: No such module "Citation/CS1".
  18. ↑ Script error: No such module "Citation/CS1".
  19. ↑ Script error: No such module "Citation/CS1".
  20. ↑ Script error: No such module "citation/CS1".
  21. ↑ Script error: No such module "Citation/CS1". ...Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors...
  22. ↑ a b Script error: No such module "Citation/CS1".
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  24. ↑ Script error: No such module "Citation/CS1".
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  26. ↑ Catalytic antibodies against cocaine and methods of using and producing same Google patents US 6566084 B1
  27. ↑ Script error: No such module "Citation/CS1".
  28. ↑ Script error: No such module "Citation/CS1".
  29. ↑ Script error: No such module "Citation/CS1".
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  33. ↑ Skeptics Stack Exchange: Is sugar one element away from cocaine (or any other drug?)
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  39. ↑ C. Dallanoce et al. - Bioorg. Med. Chem. 20 (2012) 6344-6355
  40. ↑ Script error: No such module "Citation/CS1".
  41. ↑ a b Script error: No such module "Citation/CS1".
  42. ↑ a b Script error: No such module "Citation/CS1". nih.gov article
  43. ↑ U.S. patent 6479509 Patent inventor Frank Ivy Carroll, Assignee: Research Triangle Institute
  44. ↑ U.S. patent US6479509 B1 structures given for submission, 5th compound down in image.

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External links

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Template:Phenyltropanes Script error: No such module "Navbox". Template:Chemical classes of psychoactive drugs

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