New sigma and 5-HT1A receptor ligands: omega-(tetralin-1-yl)-n-alkylamine derivatives

Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT1A affinity and moderate a affinity, were prepared in order to increase a affinity and selectivity. All new compounds are N-substituted-omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- or -omega-(1,2-dihydronaphthalen-4-yl)-n-alkylamines with, in some cases, a methoxy group on the tetralin moiety. They were tested in radioligand binding assays on sigma ([H-3]DTG and [H-3]-(+)-pentazocine), D-2 dopaminergic, 5-HT1A and 5-HT2 serotonergic, and PCP (phencyclidine) receptors. A first set of compounds bearing a 4-(1-substituted)piperazine moiety as terminal fragment on the alkyl chain showed moderate to high sigma affinity (K-i = 5.3-139 nM), the most active and selective being 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-proyl]piperazine (14), with probable pronounced alpha(2) affinity (K-i = 5.3 nM on [H-3]DTG and K-i = 71 nM on [H-3]-(+)-pentazocine). Moreover, compound 13, a 1-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and sigma affinity (K-i = 3.6 nM on [H-3]-5-HT and K-i = 7.0 nM on [H-3]DTG). The second set of compounds includes some N-phenylalkyl derivatives of 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propylamine that can be considered. to be open-chain derivatives of 4-substituted-1-arylpiperazines. Among these compounds that had a lower activity toward sigma binding sites, a high 5-HT1A affinity was found for the N-(3-phenylpropyl) derivative 21 (K-i = 4.4 nM) which demonstrated very good selectivity.