Structure activity relationships between catecholamines and the alpha-adrenergic receptor responsible for the aggregation of human platelets by epinephrine.
PEA is a potent inhibitor (Ki approximately 13 microM) of human platelet aggregation induced by epinephrine. This led us to perform an SAR study of a congeneric series of compounds in an effort to identify the molecular components of epinephrine critical to its aggregating effect upon human platelets. Phenylethanolamine was similar to PEA in inhibitory potency. However, hydroxylation of the phenyl ring diminished the inhibitory effect (Ki tyramine approximately 87 microM; Ki octopamine approximately 88 microM). Dopamine, the weakest inhibitor (Ki approximately 150 microM), 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 greater than norepinephrine greater than Epinine greater than dopamine. Phenylephrine, the prototype alpha-agonist, did not induce aggregation but was a potent inhibitor (Ki approximately 12 microM) of the aggregation induced by epinephrine. Isoproterenol, the prototype beta-agonist, was neither an aggregant nor an inhibitor of epinephrine-induced platelet aggregation. These findings suggest that the binding of epinephrine to the alpha-adrenergic receptor responsible for platelet aggregation is accomplished by the N-methyl amino group whereas intrinsic aggregating activity is a function of the catechol moiety.
D015078:2-Hydroxyphenethylamine / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D007545:Isoproterenol / Q000494:pharmacology; D008745:Methylation; D008968:Molecular Conformation; D010627:Phenethylamines / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011941:Receptors, Adrenergic / Q000494:pharmacology*; D011942:Receptors, Adrenergic, alpha / Q000494:pharmacology*
D002395:Catecholamines; D010627:Phenethylamines; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D015078:2-Hydroxyphenethylamine; D007545:Isoproterenol; D004837:Epinephrine