On the preferred rotameric conformation for dopamine agonist action: an illusory quest?

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Abstract
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 α- and β-rotameric conformations, compounds having the α-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 potent than 6,7-hydroxy- and 7,8-dihydroxycompounds. trans-7,8-Dihydroxy-1-n-propyl-1,2,3,4,4a,9,10,10b-octahydrobenzo(f)quinoline was 11 times more potent than the β-rotamer, the 6,7-dihydroxy compound, and within the trans-octahydrobenzo(g)quinoline series the α-rotameric N-propyl derivative was 467 times more potent than the β-rotamer, and the α-rotameric >N–H analogue was 46 fold more potent than the β-rotamer. Thus, the α-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 α- and β-rotamers may reflect a differential metabolism by catechol-O-methyl transferase was assessed by administration of different agonists after pyrogallol pre treatment. 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 β-rotamers to indicate a comparable potency to the α-rotameric forms.

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