Decalin Analogs of Phenethylamines as Inhibitors of Amine Uptake by Rabbit Platelets II: Uptake of 5 - Hydroxytryptamine

Abstract

<h2>Abstract:</h2> The steric aspects of the uptake of 5-hydroxytryptamine by rabbit platelets were studied utilizing the conformationally rigid decalin analogs of ephedrine and amphetamine. These analogs or their parent compounds were added to platelet-rich plasma, and their influence on the uptake of ¹⁴C-5-hydroxytryptamine was determined along with the kinetics of the process. Among the <i>β</i>- phenethanolamine-type compounds, the isomer having an axial phenyl and equatorial amino function was the most effective inhibitor and the isomer in which the phenyl and amino functions were both axial was the weakest inhibitor of uptake. In the <i>β</i>-phenethylamine series, the same cisoid isomer [(a) phenyl, (e) NH2] was the weakest inhibitor and the remaining three isomers were equipotent. The most effective cisoid decalin isomer of phenethanolamine displayed a mixed type of inhibition. The inhibition by amphetamine or <i>β</i>-phenethanolamine was also of a mixed type but was closer to competitive than to noncompetitive inhibition. Norepinephrine was a competitive inhibitor. The differences were suggested to be due to different binding of the aromatic ring. It was also suggested that lipid solubility causes the decalin derivatives to accumulate in the cell membrane and bind part of the carrier so that it is inaccessible to the substrate. Different lipid solubility would then explain the inconsistency of the most active conformation in different series. In essence, these results are in agreement with the inhibition of histamine uptake by rabbit platelets, which was earlier studied using a number of rigid and semirigid phenethylamine derivatives.