title: A 3-D model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogues of 8-hydroxy-2-(dipropylamino)tetralin.
abstract: The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.
authors.affiliation: Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Mellin
authors.forename: J
authors.initials: J
authors.lastname: Vallgårda
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: L
authors.initials: L
authors.lastname: Björk
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: N E
authors.initials: NE
authors.lastname: Andén
authors.forename: I
authors.initials: I
authors.lastname: Csöregh
authors.forename: L E
authors.initials: LE
authors.lastname: Arvidsson
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D008297:Male; D008958:Models, Molecular; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes