title: Synthesis, in vitro and in vivo 5-HT1A/5-HT2A serotonin receptor activity of new hybrid 1,2,3,4-tetrahydro-gamma-carbolines with 1-(2-methoxyphenyl)piperazine moiety.
abstract: 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 (Ki < 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.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Boksa
authors.forename: Sijka
authors.initials: S
authors.lastname: Charakchieva-Minol
authors.forename: Beata
authors.initials: B
authors.lastname: Duszyńska
authors.forename: Ryszard
authors.initials: R
authors.lastname: Bugno
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kłodzińska
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044282:Receptor, Serotonin, 5-HT1A; C040083:1-(2-methoxyphenyl)piperazine