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Copyright © 1999 by Institute of Pharmacology Polish Academy of Sciences |
Pol. J. Pharmacol., 1999, 51, 351-356 ISSN 1230-6002 |
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9-Substituted 1,2,3,4-tetrahydro-beta-carbolin-1-ones, new 5-HT1A and 5-HT2A receptor ligands.
M.J. MOKROSZ, J. BOKSA, S. CHARAKCHIEVA-MINOL, A. WESOLOWSKA, J. BORYCZ. Pol. J. Pharmacol., 1999, 51, 351-356. Three series of new 9-substituted 1,2,3,4-tetrahydro-ß-carbolin-1-ones with 2-, 3- and 4-membered alkyl chain (1, 2 and 3, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A and 5-HT2A receptor affinities and functional in vivo properties was discussed. Radioligand binding measurements showed that the majority of compounds had a distinct affinity for 5-HT1A (1b, 2a, 2b, 2c, 3b; Ki = 0.3-64 nM) and 5-HT2A receptors (1b, 2b, 2c, 3b; Ki = 0.9-80 nM). The most potent 5-HT1A (1b, 2a, 2b, 3b) and 5-HT2A (1b, 2b, 3b) ligands were evaluated in in vivo tests. The obtained results indicate that 1,2,3,4-tetrahydro-ß-carbolin-1-ones containing 1-(o-methoxyphenyl)pipera-zine (1-3b) show pharmacological profile of 5-HT1A postsynaptic antagonists (with very weak agonistic component) and 5-HT2A antagonists, compound with 1,2,3,4-tetrahydroiso-quinoline (2a) is a pure 5-HT1A postsynaptic antagonist. Summing up, the connection of 1,2,3,4-tetrahydro-ß-carbolin-1-one moiety through the 2-4-membered alkyl spacer with 1-(o-methoxyphenyl)piperazine, which is present in a variety of 5-HT1A ligands, allowed us to obtain the compounds with high and equal affinity for 5-HT1A/5-HT2A receptors and the expected functional properties, i.e. distinct antagonistic and weak agonistic activity at 5-HT1A postsynaptic receptors and antagonistic at 5-HT2A ones. Key words: 1,2,3,4-tetrahydro-ß-carbolin-1-ones, 5-HT1A and 5-HT2A receptor ligands |
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