Stereoselective interaction of tetrahydroisoquinolines in beta-adrenoceptor systems.

In selected beta1- (heart, lipolysis) and beta2-adrenoceptor (trachea) systems, the interaction of racemic-trimetoquinol (TMQ) and the erythro- and threo-diastereomers of 1-(3',4',5'-trimethoxy-alpha-hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (alpha-hydroxy TMQ) was investigated. Each tetrahydroisoquinoline possessed agonist activity in these beta-adrenoceptor systems. The rank order of potency observed for these compounds was racemic-TMQ greater than erythro-alpha-hydroxy TMQ greater than threo-alpha-hydroxy TMQ. Using isolated fat adipocytes, a favorable correlation was observed between the elevation in c-AMP and pharmacological response for the TMQ stereoisomers and diastereomers of alpha-hydroxy TMQ. The rise in intracellular c-AMP produced by (-)- and (+)-TMQ in fat cells was blocked by the presence of propranolol, and not in the presence of phentolamine. Since considerably higher concentrations (greater 10(-4) M) of these compounds were required to produce a significant inhibition of c-AMP phosphodiesterase activity in adipose tissue, it is proposed that the lipolytic response is a result of stereoselective interaction of these tetrahydroisoquinolines at the level of membrane-bound adenylate cyclase.