List of cocaine analogues

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Cocaine with its numerical substitution position locants.
2′ (6′) = ortho, 3′ (5′) = meta & 4′ = para

This is a list of cocaine analogues. A cocaine analogue is a (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:[a]

  • 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
Above: Cocaine in the chair conformation of the tropane-ring, with only its tropane locants given.

Below: Alternate two-dimensional molecular diagram of cocaine; shown specifically as a protonated, NH+, hydrochloride, and disregarding 3D stereochemistry

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.[b]

Two dimensional schematic drawing of cocaine's structural dynamic interaction points with dopamine transporter binding sites.

Although the carbmethoxy is denoted in its function as a hydrogen bond in this depiction, it has been found that it is primarily electrostatic factors which dominate binding within this space of the molecular surface area over the operative principle of hydrogen bonding.[c]

Analogs sensu stricto[]

Cocaine Stereoisomers[]

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

For any 2D strucural diagrams where steroeochemistry 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[]

183a 183b 183c
Cocaine analog 183a.svg Cocaine analog 183b.svg Cocaine analog 183c.svg
183d 4'-Fluorococaine P-ISOCOC
Cocaine analog 183d.svg 4-F'-cocaine Structure.svg P-ISOCOC.svg
Carbon 4′-hydrogen Substitutions (benzene-4′ "para" substituted benzoyloxytropanes)[e]
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

non-tropane 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
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)[3] F - - - - -
(para-Isothiocyanatobenzoylecgonine
methyl ester
)[4]
(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.[f]

meta-substituted benzoylmethylecgonines[]

184a 184b m-ISOCOC C3-Benzyloxycocaine
Cocaine analog 184a.svg Cocaine analog 184b.svg M-Isococ.svg C3benzyloxycocaine.svg
Carbon 3′-hydrogen Substitutions (benzene-3′ "meta" substituted benzoyloxytropanes)[g]
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[]

185a 185b 185c 185d
Cocaine analog 185a.svg Cocaine analog 185b.svg Cocaine analog 185c.svg Cocaine analog 185d.svg

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

Carbon 2′-hydrogen Substitutions (benzene-2′ "ortho" substituted benzoyloxytropanes)[i]
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)[5]
OAc 70 ± 1 219 ± 20 72 ± 9 3.1 1.0
185d
(2′-Hydroxycocaine)[6]
OH 25 ± 4 143 ± 21 48 ± 2 5.7 1.9
  • ɑIC50 value for displacement of [3H]cocaine

Manifold and termination benzoyloxy phenyl-substitutions[]

Vanillylmethylecgonine 186b
Hydroxymethoxycocaine.svg 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)[j]
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

Cocaine analog 186.svg 186 HO H I 215 ± 19 195 ± 10 1021 ± 75 0.9 4.7
Hydroxymethoxycocaine.svg (Vanillylmethylecgonine)[7] H OCH3 OH - - - - -
Terminating Phenyl Carbon Ring Fusions & Alterations[k]
Data-set congruent to, and aggregate with, preceding table
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name)
C=R DAT

[3H]Cocaine (IC50)

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

Benzoyl and carbomethoxy branch modifications[]

Spirocyclic benzoyl branch modification that fits criteria as a cocaine analog and a phenyltropane both (tropane 2nd locant ester rendered in given depiction shows, as has been attested, to only having been successfully alpha configured)[8]
  • Benzoylthiomethylecgonine[9]

Benzoylthiomethylecgonine.svg
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)[10]

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[]

C1 substitutions[11]
Ki values for uptake inhibition obtained on HEK-293 heterologously expressed human monoamine transporter cells.
[12]
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 ± 106 513 ± 143 358 ± 69 6.7 ± 0.3 μMd[13] "significant"[14] 6.99 ± 2.43 2.30
1-methylcocaine.svg (—)-1-methyl-cocaine Me 163 ± 23 435 ± 77 488 ± 101 "unappreciable" 1.13 μM 16.01 ± 1.90 2.67
1-ethylcocaine.svg (—)-1-ethyl-cocaine Et 95.1 ± 17.0ɑ 1,106 ± 112 598 ± 179 3.20
1-propylcocaine.svg (—)-1-n-propyl-cocaine n-Pr 871 ± 205ɑ 2,949 ± 462b 796 ± 195 3.56
1-pentylcocaine.svg (—)-1-n-pentyl-cocaine n-C5H11 1,272 ± 199b 1,866 ± 400ɑ 1,596 ± 21b 4.64
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.[15]
  • 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.[12]

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.[12]

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

2β-substitutions[]

196a (Cocaethylene) 196b 196c 196d 196e
Cocaine analog 196a.svg Cocaine analog 196b.svg Cocaine analog 196c.svg Cocaine analog 196d.svg Cocaine analog 196e.svg
196f 196g 196h 196i 196j
Cocaine analog 196f.svg Cocaine analog 196g.svg Cocaine analog 196h.svg Cocaine analog 196i.svg Cocaine analog 196j.svg
196k 196l 196m 196n 196o
Cocaine analog 196k.svg Cocaine analog 196l.svg Cocaine analog 196m.svg Cocaine analog 196n.svg Cocaine analog 196o.svg
197a 197b 197c 197d 197e
Cocaine analog 197a.svg Cocaine analog 197b.svg Cocaine analog 197c.svg Cocaine analog 197d.svg Cocaine analog 197e.svg
197f 197g
Cocaine analog 197f.svg Cocaine analog 197g.svg
Direct 2β Substitutions[l]
(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.[m] 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.[n] 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.[o] 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[p] appears to be unfounded.[q]

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.[r]

Bioisostere 2-position carbmethoxy-ester functional replacements[]

198a 198b 198c 198d
Cocaine analog 198a.svg Cocaine analog 198b.svg Cocaine analog 198c.svg Cocaine analog 198d.svg
198e 199a 199b 200
Cocaine analog 198e.svg Cocaine analog 199a.svg Cocaine analog 199b.svg Singh 200.svg
2β-isoxazole and isoxazoline ring containing analogues[s]
Data-set congruent to, and aggregate with, following tables
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
nonplanar 2β-isoxazoline ring containing analogues[t]
Data-set congruent to, and aggregate with, preceding and following tables
IC50 nM values
Structure S. Singh's
alphanumeric
assignation
R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

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


2β-isoxazoline atomically N/O reversed analogues[u]
Data-set congruent to, and aggregate with, preceding and following tables
IC50 nM values
Structure S. Singh's
alphanumeric
assignation
R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

Singh 200.svg 200 880 ± 350 400 ± 140 0.4

Vinylogous 2β-position carbmethoxy-ester functional replacements[]

201a 201b 201c 201d 201e
Cocaine analog 201a.svg Cocaine analog 201b.svg Cocaine analog 201c.svg Cocaine analog 201d.svg Cocaine analog 201e.svg
vinylogous 2β analogues[v]
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

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.[w]

Miscellaneous 2β-substituted cocaine analogues
[2H5-phenyl]-cocaine HPBE [2H3-N-methyl]-cocaine C2-ethyl-OSO2CF2
cocaine
2-[(2-methoxy-2-oxoethoxy)methyl]
cocaine
Reagent analogue rendered from its cocaine parent by replacing a cluster of several adjacent hydrogens (from among the hydrogens that comprise the entire circumference common to every basic molecular perimeter) with deuterium, in an equivalent but localized spread or cluster. Hydroxypropylbenzoylecgonine (HPBE), which imparts the topical analgesic effect in the preparation Esterom.[16] Reagent analogue used in radio-labeling ligand binding sites. caption 2-((2-methoxy-2-oxoethoxy)methyl) cocaine Structure.svg

N-modifications[]

Norcocaine (218) 219a 219b 219c
Cocaine analog 218 (norcocaine).svg Cocaine analog 219a.svg Cocaine analog 219b.svg Cocaine analog 219c.svg
219d 219e 220a 220b
Cocaine analog 219d.svg Cocaine analog 219e.svg Cocaine analog 220a.svg Cocaine analog 220b.svg
220c 220d 220e 220f
Cocaine analog 220c.svg Cocaine analog 220d.svg Cocaine analog 220e.svg Cocaine analog 220f.svg
221a 221b 221c 221d
Cocaine analog 221a.svg Cocaine analog 221b.svg Cocaine analog 221c.svg Cocaine analog 221d.svg
Nitrogen Substitutions
Mazindol comparison table
(ɑβ-CFT comparison notation)[x]
Compound S. Singh's
alphanumeric
assignation
(name)
N8-R [3H]Mazindol
binding
[3H]DA
uptake
Selectivity

Uptake/Binding

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
Miscellaneous N-modified cocaine analogues
N6 Regioisomer[17] N7 Regioisomer[17] ortho-Phenyl N7 Regioisomer[17] 8-Oxa cocaine[18]
(cf Meltzer with PTs)
(1R,3S,5S)-6-methyl-6-azabicyclo(3.2.1)octan-3-yl benzoate.svg (1S,3R,5R)-6-methyl-6-azabicyclo(3.2.1)octan-3-yl benzoate.svg (1S,3R,5R)-6-methyl-6-azabicyclo(3.2.1)octan-3-yl 2-phenylbenzoate.svg 8-Oxa Cocaine Structure.svg

Tricyclic cocaine analogues[]

8 to 2 tethered analogues[]

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes Ki (nM) [y]
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 Singh 128.svg 61.7 ± 8.5 60.3 ± 0.4 2.32 ± 0.23 2.69 ± 0.12 0.04
129 Singh 129.svg 6.86 ± 0.43 24.0 ± 1.3 1.77 ± 0.04 1.06 ± 0.03 0.07
130a Singh 130a.svg 17.2 ± 1.13 10.2 ± 1.4 78.9 ± 0.9 15.0 ± 0.4 7.8
131a Singh 131a.svg 4.00 ± 0.07 2.23 ± 0.12 14.0 ± 0.6 2.99 ± 0.17 6.3
131b Singh 131b.svg 3.61 ± 0.43 11.3 ± 1.1 25.7 ± 4.3 4.43 ± 0.01 2.3
132a Singh 132a.svg 13.7 ± 0.8 14.2 ± 0.1 618 ± 87 3.84 ± 0.35 43.5
133a 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 bridge[z]
Compound S. Singh's
alphanumeric
assignation
[3H]Mazindol [3H]DA Selectivity

Uptake/Binding

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.[aa]

8 to 3 tethered analogues[]

Thiophene tricyclic tropane analogues[19]
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
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[20]
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
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
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[]

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 sustem (light blue on right).
7-Azabicyclo[2.2.1]heptane Derivatives[ab]
Structure S. Singh's
alphanumeric
assignation
(name)
DAT
[3H]WIN 35428
Ki (nM)
(Cocaine) 89 ± 4.8
Cocaine analogue 155a.svg 155a 60400 ± 4800
Cocaine analogue 155b.svg 155b 96500 ± 42
Cocaine analogue 155c.svg 155c 5620 ± 390
Cocaine analogue 155d.svg 155d 18900 ± 1700

6/7 tropane position methoxycocaine & methoxypseudococaine analogues[]

Phenylsulfanyl, C2-C3 unsaturated nonisomeric (C2 inclusive) C4 chloro analog.[17]
Substitutions upon the 6 & 7 positions of the tropane[ac]
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
Cocaine analog 225a.svg 225a 2β, 6β-OCH3 98000 ± 12000 68000 ± 5000 0.7
Cocaine analog 225b.svg 225b 2α, 6β-OCH3 190000 ± 11000 510000 ± 110000 2.7
Cocaine analog 225c.svg 225c 2β, 7β-OCH3 4200 ± 100 6100 ± 200 1.4
Cocaine analog 225d.svg 225d 2α, 7β-OCH3 45000 ± 5000 110000 ± 4000 2.4
Cocaine analog 225e.svg 225e 2α, 7α-OCH3 54000 ± 3000 200000 ± 70000 3.7

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

211a 211b 211c 211d 211e
Cocaine analog 211a.svg Cocaine analog 211b.svg Cocaine analog 211c.svg Cocaine analog 211d.svg Cocaine analog 211e.svg
211f 211g 211h 211i 211j
Cocaine analog 211f.svg Cocaine analog 211g.svg Cocaine analog 211h.svg Cocaine analog 211i.svg Cocaine analog 211j.svg
4′-Iodococaine-2β-substituted analogues[ad]
Compound S. Singh's
alphanumeric
assignation
2β-R C2′-R IC50 (nM)
(displacement of [3H]WIN 35428)
Cocaine analog 211.svg
211a CO2OH 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
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[]

223a 223b 223c
Cocaine analog 223a.svg Cocaine analog 223b.svg Cocaine analog 223c.svg
223d 223e 223f
Cocaine analog 223d.svg Cocaine analog 223e.svg Cocaine analog 223f.svg
223g 223h 223i
Cocaine analog 223g.svg Cocaine analog 223h.svg Cocaine analog 223i.svg
3-position carbamoyl linkage substituting benzoyloxy analogues[ae]
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
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
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[]

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.)
The top image above is a 2-Dimensional emulation of the orientation for the animated 3D image to the far right, with a methoxy that is distal from the phenyl group and cis. While the alternate image below that to its bottom shown above is one with the carboxyl methyl group proximal to the phenyl, in its optimum conformation, with a likewise optimum trans configuration.

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.)[21]

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.[af] This may account for PTs increased behavioral stimulation profile over cocaine.[ag] 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.[ah]

WIN 35,065-2.svg WF-31.svg RTI-11W.svg 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.[22] (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.[23]

Various phenyltropane examples

RTI-353 structure.png RTI-150.png RTI-171 structure.png RTI-336.png
Altropane.svg Ioflupane.png Brasofensine.svg Tesofensine chemical structure.png

3β-Alkylphenyltropane & 3β-Alkenyl analogues[]

224a 224b 224c 224d 224e
Cocaine analog 224a.svg Cocaine analog 224b.svg Cocaine analog 224c.svg Cocaine analog 224d.svg Cocaine analog 224e.svg

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.[ai]

3-position alkylphenyl linkage substituting benzoyloxy analogues[aj]
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
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

6-Alkyl-3-benzyltropane analogues[]

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues[ak]
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)
Cocaine analog 229a.svg Cocaine analog 229b.svg Cocaine analog 229c.svg Cocaine analog 229d.svg Cocaine analog 229e.svg Cocaine analog 229f.svg
2α,6α-isomers:
(230a—f)
Cocaine analog 230a.svg Cocaine analog 230b.svg Cocaine analog 230c.svg Cocaine analog 230d.svg Cocaine analog 230e.svg Cocaine analog 230f.svg
2β,6β-isomers:
(231a—f)
Cocaine analog 229a.svg Cocaine analog 231b.svg Cocaine analog 231c.svg Cocaine analog 231d.svg Cocaine analog 231e.svg Cocaine analog 231f.svg
2α,6β-isomers:
(232a—f)
Cocaine analog 230a.svg Cocaine analog 232b.svg Cocaine analog 232c.svg Cocaine analog 232d.svg Cocaine analogue 232e.svg Cocaine analog 232f.svg
6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues[al]
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
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 - -
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 - -
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 - -
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-benzyltropanes[am] hide
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)
Cocaine analog 237a.svg Cocaine analog 237b.svg Cocaine analog 237c.svg Cocaine analog 237d.svg Cocaine analog 237e.svg Cocaine analog 237f.svg
6β-isomers (exo):
(238a—f)
Cocaine analog 238a.svg Cocaine analog 238b.svg Cocaine analog 238c.svg Cocaine analog 238d.svg Cocaine analog 238e.svg

Cocaine analog 238f.svg

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

above: , a DARI functional cocaine analog with structural semblance.[24] Compare the phenyltropane length tropane C2 & C3 functional group fusion variant.[25]

below:

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

2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.[26]
(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)
2,3-fused pyrimidino cocaine analogue 3a.svg
(—)-3a H C6H5 58,300 (20,200) 6140 (3350) NA
(+)-3a H C6H5 48,700 (20,100) 6030 (3400) NA
2,3-fused pyrimidino cocaine analogue 3b.svg
(—)-3b H NH2 NA NA NA
(+)-3b H NH2 NA NA NA
2,3-fused pyrimidino cocaine analogue 3c.svg
(—)-3c H CH3 NA NA NA
(+)-3c H CH3 NA NA NA
2,3-fused pyrimidino cocaine analogue 3d.svg
(—)-3d H H NA NA NA
(+)-3d H H NA NA NA
2,3-fused pyrimidino cocaine analogue 3e.svg (+/—)-3e C6H5 C6H5 30,000 (11,200) 3650 (1700) NA
  • "NA" = "no affinity", e.g. unquantifiable.

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.[26]

Piperidine cocaine-homologues[]

Tricyclo benzoyloxy dibenzene cocaine analogue. cf. benztropine compound #277, tropatepine, etc.[17]
Binding potency of piperidine homologues for displacement of [3H]WIN 35428[an]
Compound S. Singh's
alphanumeric
assignation
(name)
2β-R IC50 (nM)
(Cocaine) CO2CH3
(i.e. CO2Me)
249 ± 37
Cocaine analog 183a.svg 183a CO2CH3 2522 ± 4
Cocaine analog 242.svg 242 H 11589 ± 4
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[]

"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.[27]
Cocaine analogs which elicit noncatalytic antibodies[ao]
Compound S. Singh's
alphanumeric
assignation
(name)
2β-R
CocaineNoncatalyticHapten394.svg 394
(GNC)ɑ
CO2(CH2)5CO2H
CocaineNoncatalyticHapten395.svg 395
(Succinyl Norcocaine)[28]
CO2CH3
Cocaine hapten GNE.svg GNEb[29]
including carrier proteins:
GNE-FLiC
GNE-KLH
GNE-BSA
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
Tetrahedral-intermediate cocaine-hapten compound #400
Cocaine transition state analogues (TSAs) which generate catalytic antibodies[ap]
Compound S. Singh's
alphanumeric
assignation
(name)
R
Cocaine analog 401.svg
401a CH3
401b (CH2)5CO2H
401c CH2CO2H
401d COCH2CH2CO2H
401e H
401f CH2CH2Br
385g (CH2)2NHCO(CH2)2CONH2
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
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.[30][31][32][33]

Anti-idiotypic & butyl-cholinesterase mediated immunopharmacotherapy cocaine analogs[34]
K1-KLH/BSA[35] K2-KLH/BSA
K1-KLH-BSA.svg K2-KLH-BSA.svg

Structural/Functional intermediate analogues[]

Piperidine Analogues[]

  • JZ-IV-10 (a "Modafinil hybrid" with nocaine.[36] cf. List of modafinil analogues)

16e chemical structure.png

(+)-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.[37] 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."

  • Benzoyl-beta-D-glucoside

Benzoyl-beta-D-glucoside.svg

Benztropine (3α-Diphenylmethoxy Tropane) Analogues[]

3α-Diphenylmethoxytropane Analogues of Cocaine
Benzatropine Etybenzatropine Difluoropine (O-620) PG01053 276 277
Benzatropine Etybenzatropine Difluoropine is a stimulant drug which acts as a more selective dopamine reuptake inhibitor than cocaine. PG01053 Compound 276 Compound 277
MFZ 4-86 MFZ 2-71 3-CPMT JHW 007-d9[38] GA 103 AHN 1-055
MFZ 4-86.svg MFZ 2-71.svg 3-CPMT Deuterium labeled radio-ligand of benztropine analog JHW-007; a di-para-fluoro benztropine, and hybrid between benzatropine & difluoropine (with fluorine groups in the former to breach the difference or the latter being descarbmethoxy to approach identification with the former) N-phenylpropyl bis-4-fluorobenztropine. The 4′,4′-bisfluorinated analogue of benztropine.

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 stablize 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. [39] 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.[40][41]


3α-Diphenylmethoxy tropanes
(Benztropine analog affinities binding to DAT & DA uptake)[aq]
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 - -
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)[ar]
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
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)[as]
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
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)[at]
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
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)[42] CH2CH=CH2 - - -
(JHW 007)[42] CH2CH2CH2CH3 - - -
(GA 2-99)[42] CH2CH2NH2 - - -
(GA 103)[42] CH2CH2CH2CH2Ph - - -
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)[au]
Compound S. Singh's
alphanumeric
assignation
(name)
IC50 (nM)
DAT
(Binding of [3H]WIN 35428)
IC50 (nM)
5-HTT
(Binding of [3H]Citalopram)
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
Cocaine analog 271.svg R/S-271 2β,3α 520 >1660

Tropanyl Isoxazoline Analogues[]

Tropanyl-Δ2-isoxazoline derivatives[43]
4a 4c 5a 5c
Dallanoce 4a.svg Dallanoce 4c.svg Dallanoce 5a.svg Dallanoce 5c.svg
6a 6b 6c 7a
Dellancoe 6a.svg Dallanoce 6b.svg Dallanoce 6c.svg Dallanoce 7a.svg
7b 7c 8a 8b
Dallanoce 7b.svg Dallanoce 7c.svg Dallanoce 8a.svg Dallanoce 8b.svg
8c 9a 9b 9c
Dallanoce 8c.svg Dallanoce 9a.svg Dallanoce 9b.svg Dallanoce 9c.svg
10a 10b 10c 11a
Dallanoce 10a.svg Dallanoce 10b.svg Dallanoce 10c.svg Dallanoce 11a.svg
11b 12a 12b
Dallanoce 11b.svg Dallanoce 12a.svg Dallanoce 12b.svg

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. for such nicotinergic activity without the likewise SERT affinity).[44]

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
EXPfivesixone.png Butyltolylquinuclidine.png

Dihydroimidazoles[]

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. Beagles[av]) 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.[aw]

Local anesthetics (not usually CNS stimulants)[]

Amylocaine, or Stovaine (above), the first synthetically constructed local anesthetic. Compare structure to dimethylaminopivalophenone (below), an analgesic (opioid). Cocaine's classification as a narcotic under U.S. legal code, as has been stretched to be medicinally rationalized such when defining terms very broadly (due to its topical numbing affect, hindering pain signals from CNS recognition via local anesthesia) usually considered an exaggeration of traditional medicine naming convention, in this instance between the first synthetic sodium channel blocker and one of the very simplest opioids there remains a measure of apparent structural similarity between the former anesthetic and latter analgesic "narcotic"; despite the highly differing methods of action for the respective 'pain-killing' properties of either.[45]

In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,[46] 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.[46] 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
[47]
[47]
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[]

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.[48][49]
Cocaine HCl hydrolyzes in moist air and enucleates from on its tropane-skeleton arrangement to become the above compound; methyl benzoate
  • Coca alkaloids, the ones relating to cocaine biosynthesis include: benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, methylecgonine cinnamate, tropacocaine & truxilline
  • Cocaine metabolites (Human), which include: benzoylecgonine (BE), ecgonine methyl ester (EME), ecgonine, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE) & m-hydroxybenzoylecgonine
  • Dopaminergics
  • Federal Analog Act
  • Pharmacophore
  • Pharmacopoeia
  • Pharmacokinetics
  • Pharmacodynamics

Common analogues to prototypical D-RAs:

  • Substituted amphetamines
  • Substituted cathinones
  • Substituted phenethylamines
  • Substituted phenylmorpholines
  • Substituted methylenedioxyphenethylamines

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

  1. ^ [1]Page #969 (45th page of article) §III. ¶1. Final line. Last sentence.
  2. ^ [1]Page #1,018 (94th page of article) 2nd column, 2nd paragraph.
  3. ^ [1]Page #940 (16th page of article) underneath Table 8., above §4
  4. ^ [1]Page #970 (46th page of article) Table 27. Figure 29.
  5. ^ [1]Page #971 (47th page of article) Figure 30. & Page #973 (49th page of article) Table 28.
  6. ^ [1]Page #982 (58th page of article)
  7. ^ [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  8. ^ [1]Page #972 (48th page of article) ¶2, Line 10.
  9. ^ [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  10. ^ [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  11. ^ [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  12. ^ [1]Page #973 (49th page of article) §C. & Page #974 (50th page of article) Figure 31 & Page #976 (52nd page of article) Table 29.
  13. ^ [1]Page #974 (50th page of article) Final ¶ (5th), Second line.
  14. ^ [1]Page #975 (51st page of article) First ¶, first line.
  15. ^ [1]Page #975 (51st page of article) First ¶, 4th line.
  16. ^ [1]Page #974 (50st page of article) First (left) column, third ¶
  17. ^ [1]Page #937 (13th page of article) Second (right) column, first ¶. Above/before §2
  18. ^ [1]Page #974 (50st page of article) First (left) column, fourth ¶
  19. ^ [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  20. ^ [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  21. ^ [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  22. ^ [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  23. ^ [1]Page #976 (52nd page of article)
  24. ^ [1]Page #978 (54th page of article) §D & Page #980 (56th page of article) Figure 33 & Page #981 (57th page of article) Table 32.
  25. ^ [1]Page #964 (39th page of article) Table 23.
  26. ^ [1]Page #980 (56th page of article) Scheme 52.
  27. ^ [1]Page #963 (39th page of article) 2nd (right side) column, 2nd paragraph.
  28. ^ [1]Page #967 (43rd page of article) §C. & Page #967 (43rd page of article) Table 25
  29. ^ [1]Page #982 (58th page of article) §G & Page #983 (59th page of article) Figure 36 & Page #984 (60th page of article) Table 35.
  30. ^ [1]Page #979 (55th page of article) Table 31.
  31. ^ [1]Page #981 (57th page of article) §E & Page #982 (58th page of article) Table 33.
  32. ^ [1]Page #970 (46th page of article) §B, 10th line
  33. ^ [1]Page #971 (47th page of article) 1st ¶, 10th line
  34. ^ [1]Page #949 (25th page of article) 3rd ¶, 20th line
  35. ^ [1]Page #982 (58th page of article) 3rd ¶, lines 2, 5 & 6.
  36. ^ [1]Page #982 (58th page of article) §F, Table 34 & Figure 35.
  37. ^ [1]Page #984 (60th page of article) Figure 37.
  38. ^ [1]Page #984 (60th page of article) §H, Figure 37 & Page #985 (61st page of article) Table 36.
  39. ^ [1]Page #984 (60th page of article) Scheme 56.
  40. ^ [1]Page #986 (62nd page of article) §I, Table 37 & Scheme 58
  41. ^ [1]Page #1,014 (90th page of article) §VIII, A. Figure 59.
  42. ^ [1]Page #1,016 (92nd page of article) Figure 60.
  43. ^ [1]Page #987 (63rd page of article) §IV, Figure 39 & Page #988 (64th page of article) Table 38.
  44. ^ [1]Page #987 (63rd page of article) Figure 40, Page #988 (64th page of article) §B & Page #989 (65th page of article) Table 39.
  45. ^ [1]Page #987 (63rd page of article) Figure 41, Page #989 (65th page of article) §C & Page #990 (66th page of article) Table 40.
  46. ^ [1]Page #988 (64th page of article) Figure 42, Page #990 (66th page of article) §2 & Page #992 (68th page of article) Table 41.
  47. ^ [1]Page #988 (64th page of article) Figure 43, Page #992 (68th page of article) §3 & Table 42.
  48. ^ [1]Page #1,011 (87th page of article) §VII (7) 1st ¶.
  49. ^ [1]Page #969 (45th page of article) 2nd (right-side) column 2nd .

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