1-substituted-4-[3-(1,2,3,4-tetrahydro-5-or 7-methoxynaphthalen-1-yl)propyl]piperazines:: Influence of the N-1 piperazine substituent on 5-HT1A receptor affinity and selectivity versus D2 and α1 receptors.: Part 6

In the present paper, we report the synthesis and the binding profiles on 5-HT1A, D-2, and alpha(1) receptors of 1-substituted-4-[3-(5- or 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine derivatives 19-32 and some related heteroalkyl derivatives 33-35. The results obtained are compared to those previously reported for the 1-phenyl, 1-(2-methoxyphenyl), 1-(2-pridyl) analogues 2-9. The results pointed out the critical role of the group linked in the N-1 position of the piperazine in terms of 5-HT1A binding affinity. In fact, 1-cyclohexyl, 1-(3-benzisoxazolyl), 1-(benzothiazole-2-carbonyl), 1-(2-benzothiazolyl), 1-(2-quinolyl) substituted piperazines 21-30 displayed moderate or low 5-HT1A receptor affinity; on the contrary, 1-(3-benzisothiazolyl) and 1-(1-naphthalenyl) substituted piperazines 19, 20 and 32 displayed high 5-HT1A receptor affinity, the K-i values being in the subnanomolar range. Furthermore, compounds 19, 20 and 32 demonstrated better selectivity over alpha(1) receptors than the reference compounds 2-9. (C) 2000 Elsevier Science Ltd. All rights reserved.