Effects of some derivatives of 2-aminotetralin on dopamine-sensitive adenylate cyclase and on the binding of [ 3H]haloperidol to neuro-leptic receptors in the rat striatum

Abstract

Putative dopamine agonists from a series of 2-aminotetralin derivatives were assessed for their ability to stimulate dopamine-sensitive adenylate cyclase and to inhibit the binding of [ 3H]haloperidol to neuroleptic receptors in the rat striatum. Comparisons were made to the ability of these agents to stimulate motor function on intrastriatal injection (stereotyped biting/hyperactivity) or peripheral administration (stereotyped biting). Of the two primary amines, 2-amino-5,6-dihydroxytetralin and 2-amino-6,7-dihydroxytetralin, the 6,7-dihydroxy compound was found to be 20 times more potent than the corresponding 5,6 derivative to stimulate adenylate cyclase. The activities of a series of mono- and di-alkylated substitutes of the two primary amines (methyl, ethyl, propyl, butyl) were determined. Of particular interest, and in contrast with the primary amines, 2-( N, N-dipropyl)amino-5,6-dihydroxytetralin was shown to be twice as potent as the corresponding 6,7-derivative. Of the compounds which were shown to stimulate adenylate cyclase, little difference was found in their activities. In the second assay procedure, inhibition of [ 3H]haloperidol binding, 2-( N, N-dipropyl)amino-5,6-dihydroxytetralin was the most active compound studied (a hundred times activity of dopamine). Similarly to observations with adenylate cyclase, the 6,7- derivative was the more active of the primary amines (times ten) whilst the 5,6- derivative was the more active of the N, N-dipropylcompounds (times three). General comparisons could be made between the biochemical findings and behavioural observations: those agents most active to induce dopamine-like motor effects on subcutaneous or intrastriatal injection were generally effective to stimulate adenylate cyclase and to inhibit [ 3H]haloperidol binding, whilst compounds inactive behaviourally were also inactive in vitro [2-(amino)-5,6-dimethoxytetralin and 2-( N, N-dimethyl)amino-5,6-dimethoxytetralin]. However, an absolute correlation between in vivo and in vitro potency could not be found. The most important observation of the present studies is the potency of 2-( N, N-dipropyl)amino-5,6-dihydroxytetralin in the [ 3H]haloperidol binding assay which indicates that this 2-aminotetralin derivative may be a useful tool in future studies on dopamine receptors.