Synthesis and biological evaluation of 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine homologues at dopamine-uptake and phencyclidine- and sigma-binding sites.
Piperidine and cyclohexyl ring homologues of the high-affinity dopamine (DA) uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 3) were each prepared in four steps from the appropriate cycloalkanones. These compounds were tested for their ability to displace [3H]BTCP and [3H]cocaine and to inhibit [3H]DA uptake in rat striatal homogenates. The ratios IC50([3H]cocaine)/IC50([3H]BTCP) ranged from 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 selective of all the compounds tested for sites labeled by [3H]BTCP whereas cocaine is most selective for sites labeled by [3H]cocaine. The wide differences in the relative abilities of these compounds to displace [3H]BTCP and [3H]cocaine suggests that these two radioligands are labeling different sites on the transporter. In general, the compounds structurally related to BTCP exhibited greater selectivity for sites labeled by [3H]BTCP. However, several of the BTCP-related derivatives showed greater (compared with BTCP and cocaine) ability to displace [3H]cocaine. Most notably, 1-[1-(2-benzo[b]thienyl)cyclohexyl]pyrrolidine (7) exhibited a 3.4-fold greater affinity for these sites compared with BTCP and a 9-fold greater affinity at these sites than cocaine. Most of the BTCP homologues displayed greater ability to inhibit [3H]DA uptake in rat forebrain synaptosomes than cocaine. BTCP and 7 were the most potent of all the compounds tested in terms of their ability to inhibit uptake of [3H]DA. IC50 ratios for [3H]cocaine binding/[3H]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 identification of potential cocaine antagonists. As for BTCP, all of the compounds tested showed Ki values > 10,000 nM for displacement of [3H]TCP from rat brain homogenates. These compounds were able to displace the highly selective sigma receptor probe [3H]-(+)-pentazocine from guinea pig brain homogenates with Ki values ranging from 125 to 9170 nM. The significance of their sigma-binding activity in light of their dopaminergic properties is unclear. The diverse binding properties of these compounds at the DA-uptake site and their spectrum of inhibitory activities for [3H]DA uptake identifies them as a useful base for the development of subtype selective probes at this site. These compounds will allow further study of the structure and function of the "cocaine" receptor as well as the development of potential cocaine antagonists.
He
X S
XS
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Raymon
L P
LP
Mattson
M V
MV
Eldefrawi
M E
ME
de Costa
B R
BR
D000818:Animals; D003042:Cocaine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists; D006168:Guinea Pigs; D008297:Male; D015394:Molecular Structure; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017478:Receptors, Phencyclidine / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011759:Pyrrolidines; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; C056415:1-(1-(2-benzo(b)thienyl)cyclohexyl)piperidine; C081108:1-(1-(2-benzo(b)thienyl)cyclohexyl)pyrrolidine; D003042:Cocaine; D010622:Phencyclidine; D004298:Dopamine