title: Conformational restriction in novel NAN-190 and MP3022 analogs and their 5-HT(1A) receptor activity.
abstract: The newly synthesized analogs of NAN-190 containing m-Cl and m-CF(3) substituents in the arylpiperazine moiety and their conformationally restricted counterparts showed a very high 5-HT(1A )receptor affinity. In the LLR test, the flexible compounds 4a and 5a displayed features of a partial agonist and agonist, respectively. The conformational restriction in the tested structures caused alternations in the observed in vivo effects; compounds 4b and 5b were classified as an inactive agent and an antagonist of postsynaptic 5-HT(1A )receptors, respectively. Rigidification of MP3022 and its 5,6-dimethyl analog structures resulted in cis and trans stereoisomers 6b-9b with a 1- and 2-substituted benzotriazole moiety. In both series, in vitro experiments showed that the cis configurations of the compounds were better tolerated by 5-HT(1A) receptor sites than the trans ones. The conformational analysis revealed various spatial regions that can be explored by terminal benzotriazole fragments in those structures. Like the previously described cis-6b, the new ligand cis-7b, displayed features of a postsynaptic 5-HT(1A) receptor agonist, whereas cis-8b was characterized as a partial agonist of those receptor sites. It was suggested that the nonlinear geometry of the above agents has significant influence on the postsynaptic 5-HT(1A )receptor stimulation.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. paluchm@if-pan.krakow.pl
authors.forename: Maria H
authors.initials: MH
authors.lastname: Paluchowska
authors.forename: Ryszard
authors.initials: R
authors.lastname: Bugno
authors.forename: Sijka
authors.initials: S
authors.lastname: Charakchieva-Minol
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008046:Lip / Q000187:drug effects / Q000502:physiology; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D010879:Piperazines; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D044282:Receptor, Serotonin, 5-HT1A; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; C088974:4-(3-(benzotriazol-1-yl)propyl)-1-(2-methoxyphenyl)piperazine