Synthesis and Evaluation of Non-Catechol D-1 and D-2 Dopamine Receptor Agonists: Benzimidazol-2-one, Benzoxazol-2-one, and the Highly Potent Benzothiazol-2-one 7-Ethylamines

Article abstract of DOI:10.1021/jm00390a009

Our interest in identifying D-1 and D-2 dopamine receptor agonists that are not catechols led us to extend previous studies with oxindoles by investigating analogues of dopamine, N,N-dipropyldopamine, m-tyramine, N,N-dipropyl-m-tyramine, and epinine in which the m-hydroxyl is replaced by the NH portion of a thiazol-2-one, oxazol-2-one, or imidazol-2-one group fused to the 2,3-position.These compounds were evaluated for their affinity and agonist activity at D-1 and D-2 receptors by using in vitro assays.Replacement of the m-hydroxy in N,N-dipropyldopamine with the thiazol-2-one group resulted in a dramatic increase in D-2 receptor affinity and activity compared to that of N,N-dipropyldopamine itself or that of the corresponding oxindole, 1.The resulting compound, 7-hydroxy-4-<2-(di-n-propylamino)ethyl>benzothiazol-2(3H)-one (4), is the most potent D-2 receptor agonist reported to date in the field-stimulated rabbit ear artery (ED50=0.028 nM).The benzoxazol-2-one (6), benzimidazol-2-one (5), and isatin (51) analogues showed D-2 receptor agonist potency similar to that of 1.The des-7-hydroxy analogues of 4 (21) also has enhanced D-2 receptor activity compared to that of the corresponding oxindole, 8. 7-Hydroxy-4-(2-aminoethyl)benzothiazol-2(3H)-one, 27, a non-catechol, has enhanced D-1 and D-2 receptor activity in vitro compared to that of the corresponding oxindole, 7.In vivo, 27 increased renal blood flow and decreased blood in the dog.However, these effects were mediated primarily by D-2 receptor agonist activity.This may be a result of the D-1 partial agonist activity of 27 coupled with its potent D-2 receptor activity.