title: New 4-[omega-(diarylmethylamino)alkyl]- and 4-[omega-(diarylmethoxy)alkyl]-1-arylpiperazines as selective 5-HT1A/5-HT2A receptor ligands with differentiated in vivo activity.
abstract: Two series of novel 4-ethyl- or 4-propyl-1-arylpiperazines (5-12) with the 4,4'-disubstituted diphenylmethylamino (series a) or the diphenylmethoxy (series b) terminal fragment were synthesized and evaluated for their binding affinity at 5-HT1A and 5-HT2A receptors. The influence of the introduction of 4-methyl, 4-chloro or 4-fluoro substituents at both phenyl rings of that terminal moiety on in vitro and in vivo 5-HT1A receptor activity of those modified compounds was discussed. Compounds 5a, 6a, 9a-12a, 5b, 6b, 9b, 11b and 12b displayed high to fairly high affinity for 5-HT1A receptors (Ki = 2.4-72 nM). Compounds of both series showed low or very low 5-HT2A receptor affinity (Ki = 155-5400 nM). Amines 5a, 6a, 11a, and their ether analogs 5b, 6b and 11b, also possessed high or moderate alpha(1)-adrenoceptor affinity (K(i) = 6-104 nM). The functional activity of compounds 5a, 6a, 9a-12a, 5b, 8b, 9b, 11b and 12b was tested in vivo in the commonly used animal models. The majority of those ligands behaved like 5-HT1A receptor antagonists, their influence on the pre- and/or postsynaptic sites being diverse, though. They exhibited characteristics of partial agonists of postsynaptic 5-HT1A receptors (11a), of weak antagonists of pre- and postsynaptic sites (12a, 9b), of antagonists of presynaptic (5a) or of antagonists of postsynaptic 5-HT(1A) receptors (9a, 10a, 5b, 8b, 11b and 12b) while, 6a was devoid of functional activity at those receptors. The above findings indicate that introduction of 4-methyl, 4-chloro or 4-fluoro substituents to the diphenylmethyl part of the 1-(2-methoxyphenyl)piperazines tested in vivo may modify their 5-HT1A receptor functional activity.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Paluchowska
authors.forename: Sijka
authors.initials: S
authors.lastname: Charakchieva-Minol
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kłodzińska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists