Synthesis and dopamine receptor pharmacological evaluations on ring C ortho halogenated 1-phenylbenzazepines

A series of 1-phenylbenzazepines containing bromine or chlorine substituents at the ortho position of the appended phenyl ring (2'-monosubstituted or 2',6'- disubstituted patterns) were synthesized and evaluated for affinity towards dopamine D₁R, D₂R and D₅R. As is typical of the 1-phenylbenzazepine scaffold, the compounds displayed selectivity towards D₁R and D₅R; analogs generally lacked affinity for D₂R. Interestingly, 2',6'-dichloro substituted analogs showed modest D₅R versus D₁R selectivity whereas this selectivity was reversed in compounds with a 2'-halo substitution pattern. Compound 10a was identified as a D₁R antagonist (K_i = 14 nM; IC₅₀ = 9.4 nM).