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.
D000273:Adipose Tissue / Q000032:analysis / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000032:analysis; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D010646:Phentolamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D007546:Isoquinolines; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D000242:Cyclic AMP; D010646:Phentolamine