Structure–Activity Relationship Studies on 6-Chloro-1-phenylbenzazepines Leads to the Identification of a New Dopamine D1 Receptor Antagonist

Abstract

The 1-phenylbenzazepine template has yielded a number of D1R-like ligands, which, though useful as pharmacological tools, have significant drawbacks in terms of selectivity versus D5R as well as pharmacokinetic behavior. A number of 1-phenylbenzazepines contain a 6-chloro functional group, but extensive SAR studies around the 6-chloro-1-phenylbenzazepine framework have not been reported in the literature. To further understand the tolerance of the 6-chloro-1-phenylbenzazepine template for various substituent groups towards affinity and selectivity at D1R, we synthesized two series of analogs with structural variations at the C-7, C-8, N-3, C-3′ and C-4′ positions. The series 2 analogs differed from series 1 analogs in possessing a nitrogenated functionality at C-8 and lacked a C-4′ substituent, but were otherwise similar. Analogs were assessed for affinity at D1R, D2R and D5R. For both series, we found that the analogs lacked affinity for D2R and showed modest D1R versus D5R selectivity. For series 1 analogs, an N-3 methyl substituent group was better tolerated than N-H or an N-3 allyl substituent. The C-8 position appears to be tolerant of amino and methanesulfonamide substituents for high D1R affinity, but C-8 amides displayed low to moderate D1R affinities. A C-3′ methyl substituent appeared to be critical for the D1R affinity of some analogs, but the C-4′ substituents tried (hydroxy and methoxy; series 1) did not result in any significant boost in D1R affinity. Compound 15a was the most potent and selective D1R ligand identified from these studies (Ki at D1R = 30 nM; 6-fold selectivity versus D5R). Further functional activity assessments indicate that 15a functions as a D1R antagonist towards cAMP-mediated signaling. The predicted drug-like properties of 15a are encouraging for further pharmacological assessments on the compound.