On the preferred rotameric conformation for dopamine agonist action: an illusory quest.
Putative dopamine agonists from the 2-aminotetrahydronaphthalene and trans-octahydrobenzo (f) and (g) quinoline series were shown to inhibit the spontaneous locomotor activity of mice. Marked potency differences were observed between the alpha-and beta-rotameric conformations, compounds having the alpha-rotameric conformation having the greater potency. Thus, 2-di-n-propylmino-5,6-dihydroxytetrahydronaphthalene was 339 times more potent than the 6, 7-dihydroxy isomer, and 2-n-propylamino-5,6-dihydroxy-compound was respectively 79 times and 179 times more than 6,7-hydroxy-and 7,8-dihydroxycompounds. trans-7,8-dihydroxy-1-n-propyl-1,2,3,4,a,9,10,10b-octahydrobenzo(f)quinoline was 11 times more potent than the beta-rotamer, the 6,7-dihydroxy compound, and within the trans-octahydrobenzo(g)quinoline series the alpha-rotameric N-propyl derivative was 467 times more potent than the beta-rotamer, and the alpha-rotameric greater than N-H analogue was 46 fold more potent than the beta-rotamer. Thus, the alpha-rotamer appears the more potent in causing the present functional dopaminergic change. The dopaminergic nature of the response was indicated by its sensitivity to spiroperidol but not to yohimbine or prazosin. The possibility that a difference in behavioural potency between the alpha- and beta-rotamers may reflect a differential metabolism by catechol-O-methyl transferase was assessed by administration of different agonists after pyrogallol pretreatment. This potentiated the activity of 2-di-n-propylamino-6,7-dihydroxytetrahydro-naphthalene but not that of the 5,6-dihydroxy analogue. However, changes in the effects of N-propyl derivatives of trans-octahydrobenzo (f) and (g)quinoline were not marked and, in all experiments, pyrogallol treatment failed by orders of magnitude to shift the dose-response curves of the beta-rotamers to indicate a comparable potency to the rotameric forms.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D011804:Quinolines; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D002394:Catechol O-Methyltransferase