Southall, Noel (NCATS)
Ferrer-Alegre, Marc (NCATS)
Jansen, Daniel (Food and Drug Administration)
Henderson, Mark (NCATS)
Hu, Xin (NCATS)
Kim, David (NCATS)
This technology includes a chemical series, including the NCGC00538279 compound, that selectively activates the GHSR1a G-protein pathway for calcium mobilization while only partially activating the beta-arrestin-2 translocation pathway. The resulting chemical series may be therapeutically valuable for addictive disorders. Activation of the GHSR1a G-protein pathway promotes production and secretion of multiple hormones, including insulin, growth hormone, and IGF1. Activation of the beta-arrestin-2 pathway stimulates dopamine production and may mediate addictive behaviors. Work with non-selective antagonists in models has indicated good in vivo efficacy results for treating addictive disorders. However, long term exposure to this type of antagonist triggers multiple undesirable side effects due to their capacity to inhibit production of numerous hormones. A select antagonist has the potential to have positive therapeutic effects without the side effects.
Further optimization work could be used to produce a molecule with the selective beta-arrestin activity and improved oral bioavailability, increase CNS exposure and half-life.
This technology describes a novel selective GHSR1a Ghrelin receptor inhibitor.