Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine. Identification of Potent DAT Inhibitors Lacking the Tropane Skeleton

Abstract

To discover agents that might be useful in the treatment of cocaine abuse, we have chosen to re-explore a class of molecules that was first reported by Clarke et al. in 1973 and that was and shown to lack locomotor stimulatory activity in mice. These compounds are piperidine-3-carboxylic acid esters bearing a 4-chlorophenyl group in position 4, and as such, these structures may be viewed as truncated versions of the WIN series compounds, i.e., they lack the two-carbon bridge of the tropanes. All members of this class were synthesized starting from arecoline hydrobromide and obtained in optically pure form through resolution methods using either (+)-or (-)-dibenzoyltartaric acid. Interestingly, we have found that these piperidines do, in fact, exhibit substantial affinity in both WIN 35,428 binding at the dopamine transporter and in the inhibition of [ 3 H]dopamine uptake. Of all of the compounds synthesized, the 3-n-propyl derivative (-)-9 was found to be the most potent with a binding affinity of 3 nM. This simple piperidine is thus 33-fold more potent than cocaine in binding affinity and 29-fold more potent in its inhibition of dopamine uptake. Although no efforts have presently been made to "optimize" binding affinity at the DAT, the substantive activity found for the n-propyl derivative (-)-9 is remarkable; the compound is only about 10-fold less active than the best of the high-affinity tropanes of the WIN series. As a further point of interest, it was found that the cis-disubstituted piperidine (-)-3 is only about 2-fold more potent than its trans isomer (+)-11. This result stands in sharp contrast to the data reported for the tropane series, for the epimerization of the substituent at C-2 from to R has been reported to result in a lowering of activity by 30-200-fold. This smaller spread in binding affinities for the piperidines may reflect the smaller size of these molecules relative to the tropanes, which allows both the cis and the trans isomers to adjust themselves to the binding site on the DAT. Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken together with their reported lack of locomotor activity, provides a compelling argument for exploring this class of molecules further in animal behavioral experiments. The present work thus broadens the scope of structures that may be considered as lead structures in the search for cocaine abuse medications.

Mixed Cocaine Agonist/Antagonist Properties of (+)-Methyl 4β-(4-Chlorophenyl)-1-methylpiperidine-3α-carboxylate, a Piperidine-Based Analog of Cocaine

“…The (ϩ)-trans disubstituted piperidine, (ϩ)-CPCA, and the (Ϫ)-cis disubstituted piperidine, (Ϫ)-cis-CPCA were prepared from arecoline as described previously (Kozikowski et al, 1998). The affinity of (ϩ)-CPCA is similar to that of cocaine in inhibiting […”

“…(ϩ)-CPCA and (Ϫ)-CPCA were synthesized starting from arecoline as described previously (Kozikowski et al, 1998). The drugs were administered by dissolving their HCl salts in distilled water.…”

“…Although there is conflicting evi-dence suggesting an aversive role for serotonin in cocaine reinforcement (Richardson and Roberts, 1991;McGregor et al, 1993), we reasoned that a cocaine analog with a high affinity for DAT, but a relatively low affinity for SERT would have a pharmacological profile that would be only partially cocaine-like. In light of this, we have synthesized several piperidine-based cocaine analogs that have a relatively weak binding affinity for the SERT (Kozikowski et al, 1998). These piperidine-based molecules are truncated analogs of cocaine, or more precisely truncated analogs of the WIN series (tropane-based molecules) of compounds (Fig.…”

Recognition of Benztropine by the Dopamine Transporter (DAT) Differs from That of the Classical Dopamine Uptake Inhibitors Cocaine, Methylphenidate, and Mazindol as a Function of a DAT Transmembrane 1 Aspartic Acid Residue

“…Kozikowski and colleagues have demonstrated that piperidine-based cocaine analogs are effective in blocking binding of DAT ligands or dopamine uptake at the DAT (Kozikowski et al, 1998), indicating that the tropane ring of cocaine is not absolutely required for cocaine action at the transporter. The compound used in the present work, 4-ARA-127, is a WIN 35,428 analog that lacks the 6,7-bridgehead of the tropane ring and contains a p-chlorophenyl instead of a p-fluorophenyl substituent on what would be C-3 of the tropane ring (Fig.…”

Reinforcing Strength of a Novel Dopamine Transporter Ligand: Pharmacodynamic and Pharmacokinetic Mechanisms

“…Numerous chemical approaches have been proposed for the development of novel medications (Newman, 1998;Carroll et al, 1999). Kozikowski and colleagues have synthesized piperidinebased cocaine analogs that vary in their potencies at the monoamine transporters (Kozikowski et al, 1998;Petukhov et al, 2002). One of these compounds, (ϩ)-methyl 4␤-(4-chlorophenyl)-1-methylpiperidine-3-␣-carboxylate [(ϩ)-CPCA; Fig.…”