Inhibition of human platelet 5-hydroxytryptamine uptake by ß-phenethylamine derivatives

Forty-eight derivatives of ß-phenethylamine have been studied as inhibitors of 5-hydroxytryptamine uptake by human blood platelets in vitro. Inhibitory potency was found to be increased by para-substitution with electronegative groups, by α-methylation in the D-configuration and by addition of N-alkyl groups, and to be reduced by saturation of the ring, by ortho-methoxylation, meta- or ß-hydroxylation and by hydrazine formation. It is suggested that optimal affinity involves folding of the molecule to fit a cleft-like carrier site. The structural requirements for activity show features of similarity to those of tryptamine and tricyclic antidepressant derivatives and some resemblance with requirements for inhibition of the adrenergic uptake1 mechanism of the heart. No obvious correlation exists between the activity of these drugs as inhibitors of platelet 5-HT uptake and their ability to exert effects thought to involve central tryptaminergic mechanisms.