Discovery of a functionally selective ghrelin receptor (GHSR(1a)) ligand for modulating brain dopamine

The growth hormone secretagogue receptor-1a (GHSR(1a)) is the cognate G protein–coupled receptor (GPCR) for the peptide hormone ghrelin. GHSR(1a) is a promising therapeutic target for a wide range of metabolic, age-related, and central nervous system (CNS)–based conditions. In addition, growing evidence supports that GHSR(1a) is a modulator of dopamine (DA) homeostasis and is neuroprotective within brain DA circuits. GHSR(1a) signaling originates from pharmacologically separable G protein– and β-arrestin (βarr)–dependent pathways, and consequently, GHSR(1a)-mediated physiological responses depend upon their distinctive signaling contributions. Thus, when treating disorders of disrupted DA homeostasis, a pharmacological strategy that modulates biased GHSR(1a) signaling may uncouple desired therapeutic outcomes from unwanted side effects. Here, we report the discovery of a small molecule GHSR(1a) agonist, N8279 (NCATS-SM8864), functionally selective for G protein signaling. Comprehensive pharmacological characterization reveals that N8279 elicits potent Gα(q) activity at the apo- and ghrelin-bound GHSR(1a). Further biochemical analysis and molecular modeling demonstrate that N8279 signaling requires the extracellular domain of GHSR(1a), especially extracellular loop 2. Collectively, these findings suggest that N8279 possesses an extended binding mode into the extracellular vestibule of the GHSR(1a) that preferentially favors Gα(q) signaling over alternative G proteins and βarr2-dependent cellular responses. Critically, N8279 is brain-penetrant in mice, exhibits CNS stability, and attenuates dysfunctional DA-mediated behaviors in both genetic and pharmacological mouse models of hyperdopaminergia. Our findings provide insight into the mechanisms governing GPCR functional selectivity and emphasize how biased ligand drug development can produce novel GHSR(1a) pharmacotherapeutics to treat pathological disruptions of brain DA homeostasis.