Structural properties of phenylethylamine derivatives which inhibit transport-P in peptidergic neurones

1. Transport-P is an antidepressant-sensitive, proton-dependent, V-ATPase-linked uptake process for amines in peptidergic neurones of the hypothalamus. It is unusual in its anatomical location in postsynaptic neurones and in that it is activated by its substrate (prazosin). This study examined the structural properties of phenylethylamine derivatives which are substrates for transport-P, as judged by competitive inhibition of the uptake of prazosin 10(-6) M in immortalized hypothalamic peptidergic neurones. 2. A basic amine was essential for activity; absence of the amine or neutralization with a carboxyl group abolished activity. Primary, secondary and tertiary amines were active but quaternary and guanyl amines were inactive. 3. A phenyl group was essential for activity at transport-P. Potency at transport-P was reduced by phenolic hydroxyl groups and enhanced by phenolic halogens. Thus, for maximal potency, the phenyl group should be hydrophobic. Phenolic methoxyl groups had no effect on potency at transport-P. 4. A side chain was necessary for activity at transport-P. Potency at transport-P was reduced by beta-hydroxyl and enhanced by alpha-methyl groups. 5. These findings further distinguish transport-P from other amine uptake processes in the brain.