Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton

Alan P. Kozikowski, Gian Luca Araldi, John Boja, William M. Meil, Kenneth M. Johnson, Judith L. Flippen-Anderson, Clifford George, Eddine Saiah

Research output: Contribution to journalArticle

71 Citations (Scopus)

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 [3H]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 β to α 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.

Original languageEnglish (US)
Pages (from-to)1962-1969
Number of pages8
JournalJournal of Medicinal Chemistry
Volume41
Issue number11
DOIs
StatePublished - May 21 1998

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Tropanes
Cocaine
Skeleton
Piperidines
Pharmacology
Cocaine-Related Disorders
Locomotion
Isomers
Molecules
Dopamine
Bearings (structural)
Arecoline
Derivatives
Dopamine Plasma Membrane Transport Proteins
Carboxylic Acids
Esters
Animals
Demonstrations
Carbon
Binding Sites

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Kozikowski, A. P., Araldi, G. L., Boja, J., Meil, W. M., Johnson, K. M., Flippen-Anderson, J. L., ... Saiah, E. (1998). Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton. Journal of Medicinal Chemistry, 41(11), 1962-1969. https://doi.org/10.1021/jm980028+

Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton. / Kozikowski, Alan P.; Araldi, Gian Luca; Boja, John; Meil, William M.; Johnson, Kenneth M.; Flippen-Anderson, Judith L.; George, Clifford; Saiah, Eddine.

In: Journal of Medicinal Chemistry, Vol. 41, No. 11, 21.05.1998, p. 1962-1969.

Research output: Contribution to journalArticle

Kozikowski, AP, Araldi, GL, Boja, J, Meil, WM, Johnson, KM, Flippen-Anderson, JL, George, C & Saiah, E 1998, 'Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton', Journal of Medicinal Chemistry, vol. 41, no. 11, pp. 1962-1969. https://doi.org/10.1021/jm980028+
Kozikowski, Alan P. ; Araldi, Gian Luca ; Boja, John ; Meil, William M. ; Johnson, Kenneth M. ; Flippen-Anderson, Judith L. ; George, Clifford ; Saiah, Eddine. / Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 11. pp. 1962-1969.
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