title: 9-substituted 1,2,3,4-tetrahydro-beta-carbolin-1-ones, new 5-HT1A and 5-HT2A receptor ligands.
abstract: Three series of new 9-substituted 1,2,3,4-tetrahydro-beta-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-beta-carbolin-1-ones containing 1-(o-methoxyphenyl)piperazine (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-tetrahydroisoquinoline (2a) is a pure 5-HT1A postsynaptic antagonist. Summing up, the connection of 1,2,3,4-tetrahydro-beta-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.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
authors.forename: M J
authors.initials: MJ
authors.lastname: Mokrosz
authors.forename: J
authors.initials: J
authors.lastname: Boksa
authors.forename: S
authors.initials: S
authors.lastname: Charakchieva-Minol
authors.forename: A
authors.initials: A
authors.lastname: Wesołowska
authors.forename: J
authors.initials: J
authors.lastname: Borycz
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002243:Carbolines / Q000378:metabolism* / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008024:Ligands; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012110:Reserpine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018759:Adrenergic Uptake Inhibitors; D002243:Carbolines; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine