Design and synthesis of long-chain arylpiperazines with mixed affinity for serotonin transporter (SERT) and 5-HT(1A) receptor.

A new generation of antidepressant agents could be represented by compounds with mixed activity as serotonin transporter (SERT) inhibitors and 5-HT(1A) receptor antagonists. We report here on the synthesis and evaluation of SERT and 5-HT(1A) receptor affinity of long-chain arylpiperazines obtained either by modifying 6-nitroquipazine into a long-chain arylpiperazine or by inserting a modified 6-nitroquipazine moiety or other structures endowed with SERT affinity into a long-chain arylpiperazine with 5-HT(1A) affinity. Among the compounds studied, 2-[4-(2-methoxyphenyl)piperazin-1-yl]-N-(6-nitro-2-quinolyl)ethylamine (21) and 1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-propanone (24) showed good affinity values for SERT and 5-HT(1A) receptors (SERT: K(i) (inhibition constant)=71.8 and 62.8 nM; 5-HT(1A)K(i)=14.2 and 0.82 nM, respectively).