Partial dopamine receptor agonists with different degrees of intrinsic activity within a series of 2-(4-aminophenyl)-N,N-dipropylethylamine derivatives: Synthetic chemistry and structure-activity relationships

Article abstract of DOI:10.1016/0223-5234(96)80446-6

A series of 2-(4-aminophenyl)-N,N-dipropylethylamine derivatives were synthesized and tested for in vivo intrinsic activity at brain dopamine receptors in the rat. Differences in the sensitivity of dopamine receptors pre- and post-synaptically in the reserpine-treated rat were used to estimate the intrinsic activity of the various compounds as dopamine receptor agonists. Thus, the ability of the compounds to antagonize reserpine-induced increase in neostriatal dopamine synthesis and the suppression of spontaneous locomotor activity were taken as pre- and post-synaptic indices, respectively. The compounds in the present series display a gradient of intrinsic activity depending on the substituents in the aromatic ring. The presence of an amino group or an appropriate acylamino group in the 4-position was found to be critical for the biological activity of these compounds as agonists or antagonists. The introduction of halogen or a trifluoromethyl group in the 3-position resulted in high intrinsic activity (ie, agonist activity). The incorporation of a methyl group in the 3-position or halogens in the 3,5-positions resulted in a gradual decrease in intrinsic activity at rat brain dopamine receptors resulting in a series of compounds ranging from a full agonist to dopamine receptor blockade.