2-H- and 2-acyl-9- [omega-[4-(2-methoxyphenyl)piperazinyl]-alkyl]-1,2,3,4-tetrahydro-beta-carbolines as ligands of 5-HT1A and 5-HT2A receptors.

Three series of new unsubstituted or 2-acyl 1,2,3,4-tetrahydro-beta -carbolines (THBC), connected to 1-(o-methoxyphenyl)piperazine by 2-, 3- or 4-membered alkylene spacer (3, 4 or 5, respectively) in position 9, were synthesized and their 5-HT1A/5-HT2A receptor affinities and functional in vivo activities: were investigated. Radioligand binding studies showed that unsubstituted (a) and acyl (b-f) derivatives with prop-1,3-ylene (4) and particularly with but-1,4-ylene (5) spacer had a high 5-HT1A receptor affinity (K-i = 30-110 nM), whereas the 5-HT1A affinity of derivatives with ethylene spacer (3) was low. All those compounds (except 5c, K-i = 44 nM) did not distinctly bind to 5-HT2A receptors. The obtained results indicated that the length of an alkylene chain was a crucial parameter for determining 5-HT1A receptor affinities of the tested compounds, while acyl substituents in position 2 of THBC were not important for their 5-HT1A/5-HT2A activities. It was, also demonstrated that the few selected compounds (4d, 5a-c and 5e) with the highest affinity (K-i up to 50 nM) for 5-HT1A receptors, administered at doses of 10-20 mg/kg, behaved like antagonists of postsynaptic 5-HT1A receptors, as they reduced the 8-OH-DPAT (5-HT1A agonist)-induced lower lip retraction and behavioral syndrome in rats. Moreover, 4d seemed to be an agonist of presynaptic 5-HT1A receptors, since the hypothermia induced by its administration was attenuated by WAY 100635 (5-HT1A antagonist). Compound 5c, 5-HT2A receptor ligand, demonstrated an antagonistic activity, as it inhibited the (+/- )DOI (5-HT2A agonist)-induced head twitches in mice. The obtained results of in vivo studies suggest that introduction of different acyl substituents in position 2 of THBC with propylene or butylene spacer between tricyclous and arylpiperazine moiety is insignificant for the postsynaptic 5-HT1A receptor activity of the compounds tested in vivo. On the other hand, only compound 5c with an acryloyl group and a butylene chain behaved like a 5-HT1A/5-HT2A antagonist.