STRUCTURAL-PROPERTIES OF PHENYLETHYLAMINE DERIVATIVES WHICH INHIBIT TRANSPORT-P IN PEPTIDERGIC NEURONS

1Transport-P is an antidepressant-sensitive, proton-dependent, V-ATPas e-linked uptake process for amines in peptidergic neurones of the hypo thalamus. It is unusual in its anatomical location in postsynaptic neu rones and in that it is activated by its substrate (prazosin). This st udy examined the structural properties of phenylethylamine derivatives which are substrates for transport-P, as judged by competitive inhibi tion of the uptake of prazosin 10(-6) M in immortalized hypothalamic p eptidergic neurones. 2 a basic amine was essential for activity; absen ce of the amine or neutralization with a carboxyl group abolished acti vity. Primary, secondary and tertiary amines were active but quaternar y and guanyl amines were inactive. 3 A phenyl group was essential for activity at transport-P. Potency at transport-P was reduced by phenoli c hydroxyl groups and enhanced by phenolic halogens. Thus, for maximal potency, the phenyl group should be hydrophobic. Phenolic methoxyl gr oups had no effect on potency at transport-P. 4 A side chain was neces sary for activity at transport-P. Potency at transport-P was reduced b y beta-hydroxyl and enhanced by alpha-methyl groups. 5 These findings further distinguish transport-P from other amine uptake processes in t he brain.