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 D-2 and alpha(1) 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 so me related heteroalkyl derivatives 33-35. The results obtained are compared to those previously reported for the 1-phenyl, 1-(2-methoxyphenyl), 1-(2-p ridyl) analogues 2-9. The results pointed out the critical role of the grou p linked in the N-1 position of the piperazine in terms of 5-HT1A binding a ffinity. In fact, 1-cyclohexyl, 1-(3-benzisoxazolyl), 1-(benzothiazole-2-ca rbonyl), 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 su bnanomolar range. Furthermore, compounds 19, 20 and 32 demonstrated better selectivity over alpha(1) receptors than the reference compounds 2-9. (C) 2 000 Elsevier Science Ltd. All rights reserved.