The Discovery And Pharmacological Characterization Of An Antipsychotic Drug For GABA_B Receptor

G protein-coupled receptors(GPCR)represent the largest human superfamily of membrane protein receptors which could respond to various signaling molecules to mediate numerous intracellular physiological processes.Drugs targeting GPCR account for about one third of the currently approved drugs,which making them the most thoroughly studied and attractive drug targets.Gamma-aminobutyric acid is the major inhibitory neurotransmitter in the central nervous system,which plays a key role in regulating neuronal transmission throughout the brain and affects many physiological and mental processes.The disorder of GABA signal would break the balance of excitation and inhibition in cerebral cortex,which is one of the key factors in the pathogenesis of schizophrenia.GABA plays a physiological role mainly through ionic GABA_A/GABA_Creceptor and metabolic GABA_Breceptor.There is growing evidence that the GABA_Breceptor plays an important role in schizophrenia.Although a large number of antagonists,agonists,and positive/negative allosteric modulators have been developed for GABA_Breceptor,but only two agonists have been approved for clinical use:Baclofen for muscle spasms and alcohol addiction,and Hydroxybutyric acid(GHD)for narcolepsy.“The best way to discover a new drug is to start with an old one”.The research and development of novel drugs is a time-consuming and preciously procedure.However,drug retargeting(also known as reusing old drugs)has many advantages over new drug development.The approved drugs on the market are especially suitable for the study of drug retargeting because of their good biological activity,pharmacokinetic characteristics and safety.A deeper understanding of the mechanistic action of targeted drugs will continue to inform drug discovery,clinical trials and the overcoming of drug resistance.In this paper,we selected several clinical antipsychotic drug representatives as screening objects to explore their interaction with GABA_Breceptor.We found that one antipsychotic drug is a new negative allosteric regulator targeting GABA_Breceptor.It could act on the heterodimer interface of GABA_Breceptor,blocked the transformation of the dimer interface of seven transmembrane regions during the activation process of GABA_Breceptor,and then restrained the downstream signaling pathway of GABA_Breceptor.At the same time,we found that the drug inhibited the constitutive activity of GABA_Breceptor mutants associated with Rett syndrome,suggesting that could be a potential drug for the treatment of Rett syndrome.This study expanded the clinical use of GABA_Breceptor,provided one new case for the new use of old drugs,and promoted the development of drugs targeting GPCR.