CHEMISTRY AND PHARMACOLOGY OF THE PIPERIDINE-BASED ANALOGS OF COCAINE- IDENTIFICATION OF POTENT DAT INHIBITORS LACKING THE TROPANE SKELETON

Citation
Ap. Kozikowski et al., CHEMISTRY AND PHARMACOLOGY OF THE PIPERIDINE-BASED ANALOGS OF COCAINE- IDENTIFICATION OF POTENT DAT INHIBITORS LACKING THE TROPANE SKELETON, Journal of medicinal chemistry, 41(11), 1998, pp. 1962-1969
Citations number
20
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
41
Issue
11
Year of publication
1998
Pages
1962 - 1969
Database
ISI
SICI code
0022-2623(1998)41:11<1962:CAPOTP>2.0.ZU;2-E
Abstract
To discover agents that might be useful in the treatment of cocaine ab use, 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 locom otor stimulatory activity in mice. These compounds are piperidine-3-ca rboxylic 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 tro panes. All members of this class were synthesized starting from arecol ine hydrobromide and obtained in optically pure form through resolutio n methods using either (+)- or (-)-dibenzoyltartaric acid. Interesting ly, we have found that these piperidines do, in fact, exhibit substant ial affinity in both WIN 35,428 binding at the dopamine transporter an d in the inhibition of [H-3]dopamine uptake. Of all of the compounds s ynthesized, the 3-n-propyl derivative (-)-9 was found to be the most p otent 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 s ubstantive activity found for the n-propyl derivative (-)-9 is remarka ble; the compound is only about 10-fold less active than the best of t he high-affinity tropanes of the WIN series. As a further point of int erest, it was found that the cis-disubstituted piperidine (-)-3 is onl y about 2-fold more potent than its trans isomer (+)-11. This result s tands in sharp contrast to the data reported for the tropane series, f or the epimerization of the substituent at C-2 from beta to alpha 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 al lows both the cis and the trans isomers to adjust themselves to the bi nding site on the DAT. Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken toget her with their reported lack of locomotor activity, provides a compell ing argument for exploring this class of molecules further in animal b ehavioral experiments. The present work thus broadens the scope of str uctures that may be considered as lead structures in the search for co caine abuse medications.