OR22-2 Ghrelin Receptor (GHSR1a) Functional Selectivity As A Novel Pharmacotherapeutic Strategy To Normalize Dysfunctional Metabolic Homeostasis

Abstract The growth hormone secretagogue receptor-1a (GHSR1a) is the cognate G protein-coupled receptor (GPCR) for the orexigenic agonist ghrelin and the anorexigenic antagonist liver-expressed antimicrobial peptide-2 (LEAP2). The ghrelinergic system is activated under conditions of caloric restriction and/or environmental stress, and it acts pleiotropically to restore physiological homeostasis by modulating both central and peripheral metabolic processes, including food-seeking behavior, glycemia, energy utilization/nutrient partitioning, and cardiovascular function. Consequently, ghrelin/GHSR1a signaling provides an accessible and desirable pharmacological target. GHSR1a-mediated physiological responses rely upon distinct G protein- and β-arrestin (βarr)-dependent signaling pathways, a property referred to as 'functional selectivity' or 'biased signaling.' Thus, when treating disorders of metabolic dysfunction (e.g., obesity, type II diabetes, neurodegenerative disease), a pharmacotherapeutic strategy that modulates 'biased' GHSR1a signaling may uncouple desired therapeutic outcomes from unwanted side effects. For example, animal models bearing G protein- or βarr-biasing GHSR1a mutations may express differences in orexigenic and glucoregulatory effects that are signaling pathway-dependent, and our group has demonstrated that GHSR1a antagonism blunts cocaine-induced neuroadaptive behaviors via a mechanism requiring βarr2 in dopaminergic neurons (Toth et al., 2016, Synapse). Based on these findings and the principle of ligand functional selectivity, we sought to identify new GHSR1a drug candidates that could distinguish between G protein and βarr pathways. We discovered a GHSR1a-selective, G protein-biased agonist — N8279 (NCATS-SM8864) — based on a novel chemotype. Comprehensive pharmacological analysis revealed that N8279 elicits potent and biased Gαq activity at both the apo- and ghrelin-bound GHSR1a. Molecular modeling coupled with mutagenesis and medical chemistry supports that N8279 signals through the GHSR1a via a unique extended binding mode requiring the extracellular loop 2 and thereby, enables preferential signaling through the Gαq pathway over alternative G proteins (Gαi∕o, Gα12∕13) and βarr2. Critically, N8279 is readily brain penetrant in mice, exhibits advantageous pharmacokinetics, and attenuates aberrant dopaminergic behaviors in both genetic and pharmacological mouse models of hyperdopaminergia. Our findings together provide important insights into mechanisms governing GPCR signaling and illustrate how functional selectivity might be leveraged to develop GHSR1a pharmacotherapeutics to normalize pathological disruptions of metabolic homeostasis. Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.