Syntheses and beta-adrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analogues.
Trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] is a potent beta-adrenergic receptor agonist and inhibitor of human platelet aggregation. Selective cleavage of O-benzyl groups in the presence of an N-benzyl group using HCl and formation of a cyclic sulfite ester from the reaction of a catechol with thionyl chloride were achieved. The N-substituents included methyl, benzyl, and beta-hydroxy- and beta-chloroethyl groups. Each N-substituted TMQ caused a concentration-dependent stimulation of beta 2 (trachea) and beta 1 (atria) adrenoceptor tissues and inhibition of 15(S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13(E)-dienoic acid (U46619, a thromboxane A2 mimetic) mediated human platelet activation. TMQ remained the most potent in the series. Structure-activity results indicated that the larger the N-substituent, the lower the beta-adrenergic activity but the higher the inhibition of platelet aggregatory activity. Thus, the structural requirements of these TMQ analogues for the two types of biological activity are different.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D014213:Tretoquinol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D007546:Isoquinolines; D011943:Receptors, Adrenergic, beta; D013928:Thromboxane A2; D014213:Tretoquinol