Despite the promise of selective dopamine D1 receptor (D1R) agonists as therapeutics to treat neuropsychiatric disorders and drug abuse, there is a lack of such compounds in the clinical armamentarium. The benzazepine scaffold has proven to be a rich source of D1R agonists. However, benzazepine D1R agonists all contain a catechol motif which presents pharmacokinetic liabilities, precluding their clinical use. Previous structure-activity relationship (SAR) studies have failed to identify suitable replacements for the catechol moiety that enable retention of D1R agonist activity in benzazepines. The goal of our project is to identify novel benzazepine-based and benzazepine-inspired D1R agonists that lack a catechol moiety, as leads for drug discovery efforts towards clinically useful neuroactive drugs. In keeping with that goal, we have designed, synthesized and evaluated a set of benzazepine-based compounds that contain a diverse array of substituents and substitution patterns in the phenyl rings and nitrogen atom of the benzazepine core. In addition, we have also examined the strategy of phenyl ring replacement with heterocyclic motifs as potential catechol bioisosteres in novel benzazepine-inspired chemotypes. SAR data appears to affirm the importance of the catechol motif for D1R binding and agonist activity. Most of the modifications attempted resulted in loss of affinity and/or D1R agonist activity. In general, the presence of hydroxyl groups in ring A is preferred over methoxy groups for D1R affinity. Similarly, an N-methyl is favored as compared to N-allyl or N-unsubstituted motifs in the analogs assayed. The heterocyclic groups examined lacked affinity for the D1R. This study provides further evidence that the catechol group of D1R-preferring benzazepines is sensitive to structural modifications and has also provided some important clues as to promising modifications for retaining D1R binding and activity. We will present details of our synthetic and SAR studies.

Synthetic and biological studies of benzazepine derivatives as dopamine receptor ligands

2019 Fall National Meeting

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