Cocaine Stereoisomers 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. There are eight
stereoisomers of cocaine (excluding
mesomers and modifications to the internal portion of the tropane ring). Due to the presence of four asymmetric carbon atoms in the 1- & 5- to 8 (N) position bond bridge that could adopt
R- &
S- configurations, cocaine can be considered to have as many as sixteen stereoisomers. However, geometric constraints imparted by the bridgehead amine allow only eight to be created. The natural isomerism of cocaine is unstable and prone to
epimerization. For example, the end product of cocaine biosynthesis contains an axial C2-carbomethoxy moiety which readily undergoes
epimerization to the equatorial position via
saponification. For any 2D structural diagrams where stereochemistry is not indicated, it should be assumed the analogue depicted shares the stereochemical conformation of
R-cocaine unless noted otherwise. ===
Arene benzene-ring 2′, 3′, 4′ (5′ & 6′) position (
aryl) substitutions===
para-substituted benzoylmethylecgonines The
MAT binding pocket analogous to the lipophilic place on cocaine-like compounds, inclusive of the benzene ring, is approximate to 9
Å in length. Which is only slightly larger than a phenyl ring by itself.
meta-substituted benzoylmethylecgonines •
ɑIC50 value for displacement of [3H]cocaine
ortho-substituted benzoylmethylecgonines •
ɑIC50 value for displacement of [3H]cocaine The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.
Manifold and termination benzoyloxy phenyl-substitutions Multi-substitutions (substitutions of substitutions; e.g.
meta- & para-) or manifold ("many-fold") substituted analogues are analogues where more than one modification from the parent molecule takes place (having numerous intermediary constituents). These are created with often surprising structure–activity relationship results extrapolated therefrom. It is even a common case where two separate substitutions can each yield a weaker, lower affinity or even wholly non-efficacious compound respectively; but due to findings that oftentimes, when used together, such two mutually inferior changes being added in tandem to one analogue has the potential to make the resultant derivative display much greater efficacy, affinity, selectivity &/or strength than even the parent compound; which otherwise was compromised by either of those two alternations when made alone.
Benzoyl and carbomethoxy branch modifications •
Benzoylthiomethylecgonine 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) 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 •
ɑ,
P •
b,
P •
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. •
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. The difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the
centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6
Å for phenyltropanes and 7.7
Å for cocaine or analogs with the benzoyloxy intact. This may account for PTs increased behavioral stimulation profile over cocaine. Differences in binding potency have also been explained considering solvation effects; cocaine containing 2
β,3
β-ester groups being calculated as more solvated than the WIN-type compounds (i.e. troparil). Higher p
Kɑs of the tropane nitrogen (8.65 for cocaine, 9.55 for troparil & 11.95 for vinyl analogue
43a), decreased aqueous solvation & decreased conformational flexibility added to increased binding affinity. Despite the observation of increased stimulation, phenyltropanes lack the local anesthetic sodium channel blocking effect that the benzoyloxy imparts to cocaine. Beside topical affect, this gives cocaine an affinity for binding to sites on the dopamine and serotonin sodium dependent transport areas that are distinct & specific to MAT in contrast to the general sodium channels; creating a separate mechanism of relational affinity to the transporters in addition to its inhibition of the reuptake for those transporters; this is unique to the local anesthetic value in cocaine & analogues with a similar substitute for the benzoyloxy that leaves the sodium channel blockage ability intact. Rendering such compounds as different functionally in their relation to MAT contrasted to phenyltropane analogues which have the local anesthetic bridge removed. (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.
3β-Alkylphenyltropane & 3β-Alkenyl analogues The compound
224e, the 3
β-styrene analogue, had the highest potency in its group. While
224b &
224c showed the most selectivity, with
224b having a ten-fold greater potency for the dopamine transporter than cocaine.
6-Alkyl-3-benzyltropane analogues N.B. The benzylidene derivatives serve as synthetic intermediates for 6-Alkyl-3-benzyltropanes and have not been assayed for biological activity. Compounds
237a and
238a are the same compound as both are the parent for either series with a hydrogen saturated in their respective substitution place.
Direct 2,3-pyrimidino fused cf. strobamine (at right) for a more efficacious compound as like the below. • "
NA" = "no affinity",
e.g. unquantifiable. Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs. •
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 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. ==Structural/Functional intermediate analogues==