(+ -)-(N-ALKYLAMINO)BENZAZEPINE ANALOGS - NOVEL DOPAMINE D-1 RECEPTORANTAGONISTS/

(+/-)-(N-Alkylamino)benzazepine analogs were prepared as novel dopamin e D-1 receptor antagonists to further elucidate the role of these rece ptor subtypes in the pharmacology and toxicology of cocaine. In the fi rst series of compounds, exyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine (15) showed the highest affinity (K-i = 49.3 nM) and subtype-sel ectivity for dopamine D-1 over dopamine D-2 5-HT2a, and 5-HT2c recepto rs. Compounds 7a yl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine}, 11 xy-3-[6-[(N,N-dimethylamino)hexyl]-1-phenyl-2,3,4, 5-tetrahydro-1H-3- benzazepine-cyanoborane}, and 15 were moderately potent dopamine D-1 r eceptor antagonists as evidenced by their ability to block dopamine-st imulated adenylyl cyclase activity in rat caudate (predicted K-i value s = 60, 34, and 21 nM, respectively). Compound 7a appears to be unique in that, despite its relatively potent inhibition of dopamine stimula ted adenylyl cyclase, it demonstrated relatively weak binding affinity at the dopamine D-1 receptors (K-i = 811 nM). Unlike previously repor ted N-alkylbenzazepines, where a significant loss in dopamine D-1 rece ptor binding affinity was observed when successive increases in the al kyl side chain size at the benzazepine nitrogen were made, several of these novel N-alkylamino analogs demonstrated high-affinity binding wi th an optimal chain length of six carbons. This initial series of comp ounds appears to be identifying another binding domain on the dopamine D-1 receptor protein that has not previously been characterized and t hat accepts an amino function. Further, these compounds may serve as t emplates for the design of peripherally active dopamine D-1 receptor a ntagonists.