Targeting -opioid Receptor-Galanin Gal1 Receptor Heterodimers for the Treatment of Opioid Use Disorder (OUD)

National Center For Advancing Translational Sciences

Investigators

Abstract

Mu-opioid receptors (MOR) mediate both the analgesic and addictive effects of opioids. Galanin, a neuropeptide, exerts analgesic effects by acting on galanin Gal1 receptors (Gal1R) localized in the spinal cord. Dr. Ferre discovered that galanin counteracts the addictive effects of opioids by acting on Gal1R that forms complexes (heteromers) with MOR localized in the mesencephalon; additionally, Gal1R mediates the dopaminergic effects of opioids. The project aims to discover potent and selective Gal1R ligands with the ability to cross the blood-brain barrier, which could provide strong analgesia with low abuse liability when combined with opioids. The project combines the collaborative team’s expertise and capabilities of implementing state-of the art methods to obtain new compounds for druggable targets, including high-throughput screening (HTS), medicinal chemistry, and biological models of analgesia and opioid reward. Previously, the team conducted extensive qHTS and screened over 183,000 compounds. The team also screened over 150,000 natural products fractions from the NCI Natural Products Library; confirmation testing is complete, but the selective hits’ potency was low. From the small molecule qHTS, the team identified two selective agonist chemotypes and one positive allosteric modulator (PAM-1). They are focused on the most promising chemotype, “Chemotype-1.” Chemotype-1 is a β-arrestin biased full agonist. Structure-activity-relationship (SAR) studies are underway. Several analogs were found in NCATS’ libraries and tested. The medicinal chemistry team also designed and synthesized over 130 new analogs, enabling comprehensive exploration of the molecule’s key functional domains. As a result, they were able to improve both the potency (~40-fold) and efficacy (~100%) while maintaining the selectivity for GALR1. The SAR campaign is ongoing to further improve the potency and drug-like properties, such as metabolic stability and brain exposure. (They also designed and made PAM-1 analogs, but the potency was only improved ~2-fold). The most potent Chemotype-1 analog was resynthesized and sent to our collaborator at University of California San Francisco for co-crystallization with GALR1. To complement the medicinal chemistry campaign, the team informatician conducted a binding model analysis of the lead series for structure-based lead optimization, a structural comparison of GALR1/ GALR2/ GPR151 for selectivity and mutagenesis studies, as well as structure-based peptide design for an antagonist (GALR1 His267). The team has published some of their important findings in two papers (PMID: 35750299, 40616201