N8279 (NCATS-SM8864) is a selective, brain-penetrant small molecule Gαq-biased GHSR1a agonist with binding IC50 of 1.3 uM.
N8279 is nearly an order of magnitude (8.9-fold) more potent than the endogenous ligand ghrelin and is a full agonist.
iCa2+ EC50 of N8279 is 41-fold more potent than its GHSR1a binding IC50, suggesting possible allosteric activity, which could be competitively inhibited by GHSR1a antagonists YIL781 and JMV2959.
N8279 is a weak activator of GHSR1a-mediated, βarr2-dependent cellular responses relative to ghrelin.
N8279 requires receptor sites and/or conformational states driven by the GHSR1a ECD that are distinct from ghrelin.
N8279 is brain-penetrant and attenuates aberrant DAergic behavior in mice.
