title: The influence of modifications in imide fragment structure on 5-HT(1A) and 5-HT(7) receptor affinity and in vivo pharmacological properties of some new 1-(m-trifluoromethylphenyl)piperazines.
abstract: New, flexible (7, 9, 11 and 13) and rigid (8, 10, 12 and 14) imides with a 1-(m-trifluorophenyl)piperazine fragment and a tetramethylene or a 1e,4e-cyclohexylene spacer, respectively, showed very high affinity (K(i)=0.3-34 nM) and agonistic in vivo activity for 5-HT(1A) receptors. Flexible new compounds and the previously described 5 also bound to 5-HT(7) receptors (K(i)=21-134 nM). Selected glutarimide derivatives, that is, the most potent postsynaptic 5-HT(1A) receptor agonist rigid compound 8 and its flexible analogue 7, as well as the previously described full agonist-rigid compound 6 and the partial agonist-its flexible counterpart 5 exhibited moderate affinity for alpha(1)-adrenoceptors (K(i)=85 - 268 nM), but were practically devoid of any affinity for dopamine D(2) sites. Those glutarimides demonstrated anxiolytic- (5 and 7) and antidepressant-like (5, 6 and 8) activity in the four-plate and the swim tests in mice, respectively; at the same time, however, they inhibited the locomotor activity of mice. The antidepressant-like effect of 8 was significantly stronger than that induced by imipramine used as a reference antidepressant.
authors.affiliation: Department of Medicinal Chemistry, Polish Academy of Science, Smetna 12, 31-343 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: Beata
authors.initials: B
authors.lastname: Duszyńska
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Nikiforuk
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lenda
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000818:Animals; D001831:Body Temperature; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007094:Imides / Q000737:chemistry*; D008024:Ligands; D008046:Lip / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013550:Swimming