Peripheral dopamine receptors.

Since 1979 when two subtypes of peripheral dopamine receptors (DA1 and DA2) were first proposed, much progress has been made to confirm such a view. Cumulative experience with the dog in vivo models suggests that the potency order: fenoldopam greater than dopamine greater than dipropyl dopamine greater than apomorphine characterizes the DA1 receptor while the reverse order: apomorphine greater than dipropyl dopamine greater than or equal to dopamine much greater than fenoldopam distinguishes the DA2 subtype. SCH 23390 for the DA1 and domperidone and (S)-sulpiride for the DA2, as selective antagonists, clearly identify the two subtypes. Increase in cyclic AMP after DA1 activation and decrease after DA2 occupancy have been reported. However, how both increase and decrease in cyclic AMP transduce vascular relaxation remains to be explained. DA1 and DA2 agonist activities of two new structures, CY 208,243 (Sandoz) and dihydrexidine, are reported in this chapter. Addition of benzene to ergoline and benzoquinoline moieties rendered these molecules inactive on the DA2 receptor while bestowing DA1 agonist activity on these otherwise inactive molecules and even obviated the need for two OH groups for DA1 activity. It would appear that the current views on structural requirements for DA1 and DA2 agonist activities will require revision and reexamination.