SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-[1-(2-BENZO[B]THIENYL)CYCLOHEXYL]PIPERIDINE HOMOLOGS AT DOPAMINE-UPTAKE AND PHENCYCLIDINE-BINDING AND SIGMA-BINDING SITES

Piperidine and cyclohexyl ring homologues of the high-affinity dopamin e (DA) uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 3) were each prepared in four steps from the appropriate cycloa lkanones. These compounds were tested for their ability to displace [H -3]-BTCP and [H-3]cocaine and to inhibit [H-3]DA uptake in rat striata l homogenates. The ratios IC50([H-3]cocaine)/IC50 ([H-3]BTCP) ranged f rom 62 for BTCP to 1.5 for 1-[2-(benzo[b]thienyl)-cyclopentylamine (17 ); cocaine gave a ratio of 0.6. This indicates that BTCP is the most s elective of all the compounds tested for sites labeled by [H-3]BTCP wh ereas cocaine is most selective for sites labeled by [H-3]cocaine. The wide differences in the relative abilities of these compounds to disp lace [H-3]BTCP and [H-3]cocaine suggests that these two radioligands a re labeling different sites on the transporter. In general, the compou nds structurally related to BTCP exhibited greater selectivity for sit es labeled by [H-3]BTCP. However, several of the BTCP-related derivati ves showed greater (compared with BTCP and cocaine) ability to displac e [H-3]cocaine. Most notably, 1-[1-(2-benzo[b]thienyl)cyclohexyl]pyrro lidine (7) exhibited a 3.4-fold greater affinity for these sites compa red with BTCP and a 9-fold greater affinity at these sites than cocain e. Most of the BTCP homologues displayed greater ability to inhibit[H- 3]DA uptake in rat forebrain synaptosomes than cocaine. BTCP and 7 wer e the most potent of all the compounds tested in terms of their abilit y to inhibit uptake of [H-3]DA. IC50 ratios for [H-3]cocaine binding/[ H-3]DA uptake ranged from 0.47 for 1-[1-(2-benzo[b]thienyl)cyclopentyl ]homopiperidine (11) to 8.8 for 1-(2-benzo[b]-thienyl)cyclohexylamine( 4). The importance of this ratio remains unclear in terms of identific ation of potential cocaine antagonists. As for BTCP, all of the compou nds tested showed K(i) values > 10 000 nM for displacement of [H-3]TCP from rat brain homogenates. These compounds were able to displace the highly selective a receptor probe [H-3]-(+)-pentazocine from guinea p ig brain homogenates with K(i) values ranging from 125 to 9170 nM. The significance of their sigma-binding activity in light of their dopami nergic properties is unclear. The diverse binding properties of these compounds at the DA-uptake site and their spectrum of inhibitory activ ities for [H-3]DA uptake identifies them as a useful base for the deve lopment of subtype selective probes at this site. These compounds will allow further study of the structure and function of the ''cocaine' r eceptor as well as the development of potential cocaine antagonists.