New 3-[4-(aryl)piperazin-1-yl]-1(benzo[b]thiophen-3-yl) propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants

A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl) piperain-1-yl]propan-1-ol (8) show values (nM) of K-i = 30 and 2.3 for 5-HT1A receptors and K-i = 30 and 12 for serotonin transporters, respectively. In GTP gammaS binding assays, compound 8 revealed antagonist properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action. (C) 2001 Editions scientifiques et medicales Elsevier SAS.