Rational Discovery of A Dual Dopamine Receptor Modulator for Efficient Antipsychotic Therapy

摘要

A major challenge in treating schizophrenia is developing drugs that normalize both subcortical and cortical dopamine signaling.Here,we reveal that (-)-stepholidine (l-SPD)uniquely achieves this through D1 receptor activation and D2 receptor inhibition.High-resolution structures of l-SPD bound to D1R and D2R reveal a remarkable molecular mechanism where subtle differences in extracellular vestibules enable opposite functional outcomes.This structural insight enabled development of VV009,which maintains l-SPD’s dual pharmacology while overcoming its long-standing limitations in bioavailability and brain penetration.VV009 demonstrates robust efficacy against positive,negative,and cognitive symptoms in rodent models at low dosage with minimal side effects.Beyond providing a promising clinical candidate,this work enhances the understanding of dopamine receptor pharmacology and establishes a new paradigm for rationally designing nextgeneration antipsychotics that leverage dual receptor modulation to achieve optimal therapeutic outcomes for schizophrenia,potentially transforming treatment for this devastating disorder.

关键词

Dopamine receptors / (-)-stepholidine / dual pharmacology / drug design / schizophrenia