Trans-4-[4-(methoxyphenyl)cyclohexyll-1-arylpiperazines:: A new class of potent and selective 5-HT1A receptor ligands as conformationally constrained analogues of 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-arylpiperazines

The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D-2, and alpha (1) receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)-cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be-considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K-i, nM: 5-HT1A = 0.028, D-2 = 2194, alpha (1) = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D-2, and alpha (1) receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D-2 and alpha (1) receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha (1a), alpha (1b), alpha (1d) receptor subtypes. They were also submitted to the [S-35]GTP gammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K-i) and in vitro activity (pD'(2)) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.