Design, synthesis and properties of several heterocyclic dopaminergic ligands

Two series of non-catechol dopamine (DA) bioisosteres with the hydroxyl groups on the benzene ring replaced by N-H groups were synthesized using phenethylamine as a parent molecule. Compounds from the first series (1-9) contained a primary amine group, while those from the second one (10-19) had a N,N-di-propylamino group introduced into the side chain of the phenethylamine. The affinity and selectivity of these compounds for the D-1 and D-2 subtypes of the DA receptor were determined in competition binding assays using synaptosomal membranes from bovine caudate nuclei and [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) as radioligands. None of the 19 compounds examined expressed significant affinity for D-1 receptors, while compounds 15, 17 and 19, in this order of potency, strongly competed with [3H]spiperone binding to D-2 receptors under conditions that prevented radioligand binding to serotonin 5HT2 receptors. Varying affinities of the compounds examined for the DA receptors can be ascribed to different acidity of the N-H groups introduced at meta- and para-positions of the phenethylamine molecule.