Decalin Analogs of Phenethylamines as Inhibitors of Amine Uptake by Rabbit Platelets I: Uptake and Distribution of Histamine

Abstract

The importance of conformation with regard to the inhibition of histamine uptake by platelets was studied utilizing different conformationally rigid and semirigid inhibitors. Rabbit blood platelets were incubated in plasma for 80 min with 10−6 M14 C-histamine, and the total accumulation of radioactivity with or without inhibitors was determined. Four different series were studied. The parent substances were β-phenethylamine, JV-isopro- pyl-β-phenethylamine, β-hydroxy-β-phenethylamine, and N-iso-propyl-tf-hydroxy-tf-phenethylamine. These structures were made conformationally rigid by incorporating the functional groups into the 2- and 3-positions of the trans- decalin molecule. The semirigid systems were studied using cyclohexane and erythro- and threo- butane analogs of the parent compounds. In three of the four decalin series, the most active conformation was found to have an axial phenyl and equatorial amino group. In one series, both phenyl and amino groups were equatorial in the most active isomer. Thus in all cases the active conformation possessed a gauche -relationship. The semirigid systems did not give consistent results, which could be due partly to their flexibility which makes it impossible to deduce the principal conformation in the binding mode. Most substances studied were racemic mixtures; the d- and /-forms of amphetamine were tested separately, and the d- form was slightly more active at low concentrations. The preferred conformation for uptake inhibition in most cases appears to have the phenyl and amino groups at a dihedral angle of approximately 60°, but the differences are not outstanding, which may at least in part be due to the addition of a bulky lipophilic group to the phenethylamine structures.