Scientists uncover new and “unexpected” information about schizophrenia drug
14 September 2023
Cryo-EM map of the M4 mAChR in complex with G proteins bound to xanomeline. Nature Communications
Drug discovery researchers from Monash University have uncovered new, and unexpected, information about ‘xanomeline’, a potential-first-in class drug currently progressing through Phase III clinical trials for the treatment of patients with schizophrenia.
Xanomeline has a rich clinical history in neuropsychopharmacology, and prior studies of its ‘atypical’ pharmacology had highlighted the potential role of specific subtypes of the muscarinic acetylcholine receptor (mAChR) family of G protein-coupled receptors (GPCRs) in its potential therapeutic effects.
Xanomeline activates mAChRs in the brain, especially the M4 mAChR subtype, which regulates neurotransmitters, such as dopamine and glutamate, known to be imbalanced in people living with neuropsychiatric and neurological diseases, including schizophrenia.
The new study, published in the prestigious journal, Nature Communications, was led by Dr David Thal, Dr Celine Valant and Professor Arthur Christopoulos from the Monash Institute of Pharmaceutical Sciences (MIPS), and Associate Professor Ron Dror, from Stanford University.
The multidisciplinary collaboration revealed, for the first time, the three dimensional structure of xanomeline bound to its primary target, the M4 mAChR, determined using cryo-electron microscopy (cryo-EM). The main, and unexpected, finding of the study was that two molecules of xanomeline were observed to simultaneously bind to a single M4 mAChR; one xanomeline molecule within the primary ‘orthosteric’ site recognised by the receptor’s endogenous agonist, and a second allosteric molecule concomitantly occupying a spatially distinct ‘allosteric’ site, which can modulate the activity of orthosteric drugs.
This is the first time that such a finding has been observed and validated for any GPCR, let alone for one bound to a late-stage clinical drug candidate.
MIPS’ Dr David Thal, said that understanding how xanomeline specifically interacts with the therapeutically relevant M4 mAChR subtype is key for designing future novel and more targeted first-in-class antipsychotics.
“Recent studies suggest xanomeline’s antipsychotic efficacy is primarily mediated by the M4 mAChR. In what we believe to be a world-first, the identification of a novel dual binding mode for xanomeline based on our cryo-EM structure may thus shed new light on the actions of a new class of clinical drug candidate for the treatment of schizophrenia, and highlight the power of structural biology techniques, like cryo-EM, for providing new insights into pharmacology and drug discovery.”
Schizophrenia is a debilitating and complex psychiatric disease, however the development of new safe and effective medicines to improve the lives of those living with schizophrenia has remained stagnant for decades.
Professor Arthur Christopoulos, FAA FAHMS, Dean of the Faculty of Pharmacy and Pharmaceutical Sciences, highlighted that the identification and characterisation of both orthosteric and allosteric binding modes for the same drug at a single GPCR is a clear point of differentiation from previous drug-bound GPCR structures, and may represent an exciting new pathway for drug development to help those living with the broad spectrum of symptoms associated with schizophrenia that are currently poorly treated by existing antipsychotics.
Dr Celine Valant added, “the extent to which this novel mode of ‘dual-site, single-target’ simultaneous drug engagement translates to other GPCRs remains to be determined. Nonetheless, the demonstration that a late-stage clinical GPCR drug candidate can engage both orthosteric and allosteric sites represents a novel finding and clear basis for further understanding of xanomeline's complex pharmacology”.
In addition to the MIPS and Stanford teams, the study involved an international team of researchers including University of Glasgow; Boston-based Karuna Therapeutics, and the University of Tokyo.
Other MIPS researchers include Professor Denise Wootten, Professor Patrick Sexton, Dr Wessel Burger, Dr Vi Pham, Dr Ziva Vuckovic, Alexander Powers, Dr Jesse Mobbs and Dr Alisa Glukhova.
ENDS