NNC-112, NNC-687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists

Abstract The neurochemical properties of three novel benzazepine derivatives NNC-112, NNC-687 and NNC-756 were assessed. These compounds inhibited dopamine D 1 receptor binding in vitro with low nanomolar to picomolar dissociation constants whereas those for the D 2 receptor were in the micromolar range. Contrary to classical neuroleptics, but similar to the atypical neuroleptics, clozapine and fluperlapine, NNC-112, NNC-687 and NNC-756 were relatively more potent in inhibiting dopamine-stimulated adenylyl cyclase than [ 3 H]SCH 23390 binding. Both NNC-112 and NNC-756 had high affinity for the 5-HT 2 receptor whereas NNC-687 had low affinity for this receptor. The affinity for other receptors or neurotransmitter transporters was very low. In vivo, the dopamine D 1 receptor selective profile of NNC-112, NNC-687 and NNC-756 was evident from the potent inhibition of D 1 receptor binding whereas no effect on D 2 receptor binding was apparent. In addition, the compounds blocked D 1 receptor-mediated rotation in unilaterally 6-hydroxydopamine-lesioned rats, but had no effect on D 2 -induced rotation. Thus, NNC-112, NNC-687 and NNC-756 are potent and selective dopamine D 1 receptor antagonists that may be useful in the treatment of schizophrenia.