Towards metabolically stable 5-HT receptor ligands: a study on 1-arylpiperazine derivatives and related isosters.

Serotonin 7 (5-hydroxytryptamine7 or 5-HT) is the most recently identified serotonin receptor. It is involved in mood disorders and is studied as a target for antidepressants. Here, we report on the structural manipulation of the 5-HT receptor ligand 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine ( 1a) aimed at obtaining 5-HT receptor ligands endowed with good in vitro metabolic stability. A set of N-[3-methoxyphenyl)ethyl-substituted] 1-arylpiperazine, 4-arylpiperidine and 1-aryl-4-aminopiperidine was synthesized and tested in radioligand binding assays at human cloned 5-HT and 5-HT receptors. In vitro metabolic stability of the target compounds was assessed after incubation with rat hepatic S9 microsomal fraction. Among the new compounds, 1-(2-biphenyl)-4-[2-(3-methoxyphenyl)ethyl]piperazine ( 1d) and 4-(2-biphenyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine ( 2d) showed a good compromise between affinity at 5-HT receptor ( K = 7.5 nM and 13 nM, respectively) and in vitro metabolic stability (26 and 65 % recovery of parent compound, respectively) but were poorly selective over 5-HT receptor. [ABSTRACT FROM AUTHOR]