STRUCTURE ACTIVITY RELATIONSHIPS BETWEEN CATECHOLAMINES AND THE ALPHA-ADRENERGIC RECEPTOR RESPONSIBLE FOR THE AGGREGATION OF HUMAN PLATELETS BY EPINEPHRINE
PEA [phenylethylamine] is a potent inhibitor (Ki .apprx. 13 .mu.M) of human platelet aggregation induced by epinephrine. SAR [structure-activity relationship] study of a congeneric series of compounds was performed to identify the molecular components of epinephrine critical to its aggregating effect upon human platelets. Phenylethanolamine was similar to PEA in inhibitory potency. Hydroxylation of the phenyl ring diminished the inhibitory effect (Ki tyramine .apprx. 87 .mu.M; Ki octopamine .apprx. 88 .mu.M). Dopamine, the weakest inhibitor (Ki .apprx. 150 .mu.M), was a partial agonist capable of inducing platelet aggregation in some samples of PRP. The order of potency of catecholamines as aggregating agents was epinephrine > norepinephrine > epinine > dopamine. Phenylephrine, the prototype .alpha.-agonist, did not induce aggregation but was a potent inhibitor (Ki .apprx. 12 .mu.M) of the aggregation induced by epinephrine. Isoproterenol, the prototype .beta.-agonist, was neither an aggregant nor an inhibitor of epinephrine-induced platelet aggregation. The binding of epinephrine to the .alpha.-adrenergic receptor responsible for platelet aggregation is apparently accomplished by the N-methyl amino group; intrinsic aggregating activity is a function of the catechol moiety.