NNC-112, NNC-687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists.
The neurochemical properties of three novel benzazepine derivatives NNC-112, NNC-687 and NNC-756 were assessed. These compounds inhibited dopamine D1 receptor binding in vitro with low nanomolar to picomolar dissociation constants whereas those for the D2 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 [3H]SCH 23390 binding. Both NNC-112 and NNC-756 had high affinity for the 5-HT2 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 D1 receptor selective profile of NNC-112, NNC-687 and NNC-756 was evident from the potent inhibition of D1 receptor binding whereas no effect on D2 receptor binding was apparent. In addition, the compounds blocked D1 receptor-mediated rotation in unilaterally 6-hydroxydopamine-lesioned rats, but had no effect on D2-induced rotation. Thus, NNC-112, NNC-687 and NNC-756 are potent and selective dopamine D1 receptor antagonists that may be useful in the treatment of schizophrenia.
Andersen
P H
PH
Department of Molecular Pharmacology, Biosciences, CNS Division, Novo Nordisk, Bagsvaerd, Denmark.
Grønvald
F C
FC
Hohlweg
R
R
Hansen
L B
LB
Guddal
E
E
Braestrup
C
C
Nielsen
E B
EB
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism
D001552:Benzazepines; D001572:Benzofurans; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; C077123:NNC 112; C077122:5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol; D012701:Serotonin; C075357:odapipam; D004298:Dopamine