Synthesis, in vitro and in vivo 5-HT1A/5-HT2A serotonin receptor activity of new hybrid 1,2,3,4-tetrahydro-γ-carbolines with 1-(2-methoxyphenyl)piperazine moiety

A series of 15 new 2-H- and 2-substituted 5-{omega-[4-(2-methoxyphenyl)piperazinyl]-alkyl}-1,2,3,4-tetrahydro-gamma-carboline derivatives were prepared, and their affinity for 5-HT1A and 5-HT2A serotonin receptors was determined. Most of those hybrid compounds were found to bind with high affinity to 5-HT1A sites (K-i < 50 nM; 2d, 3a, 3b, 3d, 3e, 4b, 4d, 4e) and moreover two of them (4d, 4e) were mixed 5-HT1A/5-HT2A ligands. The results of a lower lip retraction test in rats indicated that the 2-acetyl derivative with a dimethylene spacer (2d) had features of a postsynaptic 5-HT1A receptor agonist, whereas its analogues with longer chains (3d and 4d) behaved like antagonists. Both 5-HT2A receptor ligands (4d, 4e) at high doses inhibited the (+/-)-DOI-induced head twitches in mice And were classified as weak antagonists of those receptors.