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

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127305. doi: 10.1016/j.bmcl.2020.127305.

Rajan Giri ¹, Hari K Namballa ², Ananta Sarker ², Ian Alberts ³, Wayne W Harding ⁴

Affiliations

1 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Chemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA.
2 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA.
3 LaGuardia Community College, Department of Chemistry, 31-10 Thompson Avenue, LIC, NY 11104, USA.
4 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Chemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA; Program in Biochemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA. Electronic address: whardi@hunter.cuny.edu.

PMID: 32631525 DOI: 10.1016/j.bmcl.2020.127305

Abstract

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).

Keywords

Benzazepine; D1; D2; D5; Dopamine.

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