Identification and Characterization of ML321: A Novel and Highly Selective D₂ Dopamine Receptor Antagonist with Efficacy in Animal Models That Predict Atypical Antipsychotic Activity.

ABSTRACT: We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R and to a lesser extent the D3R, demonstrating excellent receptor selectivity. The D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in non-human primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dose-dependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3

SUBMITTER: Free RB 

PROVIDER: S-EPMC9841785 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature