Optimization of ML321: a D 2 dopamine receptor‐selective antagonist for the treatment of neuropsychiatric disorders
The FASEB Journal(2021)
摘要
FDA-approved antipsychotics treat the positive symptoms of schizophrenia by targeting and blocking the D2 dopamine receptor (D2R). However, current treatment is hindered by numerous side-effects due to off-target activities at other GPCRs and unfavorable binding kinetics at the D2R. We have identified a lead antipsychotic candidate, ML321, using high throughput screening to identify selective D2R antagonists. ML321 demonstrates global selectivity for inhibiting the D2R, and to a lesser extent the D3R, with little activity at other GPCR targets. Additionally, ML321 has optimal binding kinetics at the D2R with slow association and fast dissociation rates to/from the receptor – properties that may limit commonly observed extrapyramidal side effects (EPS). In fact, ML321 does not produce catalepsy in rodents, a behavior that models the EPS observed with many antipsychotics. Moreover, behavioral assays demonstrate that ML321 is effective in animal models that are predictive of antipsychotic efficacy in humans (e.g., attenuation of both amphetamine and PCP-induced locomotor activity and pre-pulse inhibition). Importantly, no other D2R antagonist exhibits this pharmacological and behavioral profile supporting its development into an advanced drug lead. No concerns were noted during safety/toxicity studies including hERG channel activation, cytotoxicity, the AMES test, and a CYP inhibition study. While a promising therapeutic, it has a short metabolic half-life, impeding its clinical development. To this end, we have determined the metabolic ID of ML321 and designed, synthesized, and tested a series of ML321 analogs with modifications of the site of primary metabolism (the alkyl-thiophene moiety) in an effort to metabolically stabilize the scaffold while maintaining its favorable pharmacological properties. Over 55 ML321 analogs have been synthesized and pharmacologically characterized using radioligand binding and functional b-arrestin recruitment assays. Simultaneously, in vitro ADME properties including metabolic stability, permeability, and solubility have been determined for each analog. These studies have led to the optimization of the compound into a collection of lead clinical candidates that show similar pharmacology to ML321 but with marked increases in metabolic stability and ADME properties. These findings refine our understanding of ML321 structure-activity relationships, particularly around the alkyl-thiophene moiety. Based on this information, additionally optimized analogs have been designed and synthesized supporting the notion that ML321 can be developed into an advanced drug lead with the potential to be a superior therapeutic for the treatment of schizophrenia and other psychotic disorders.
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关键词
dopamine,ml321,receptor‐selective,disorders
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