Identification of Novel Small Molecule Antagonists of the Neuropeptide-S Receptor

There is a clear need to discover novel small molecule antagonists of the neuropeptide S receptor (NPSR) to help probe NPS/NPSR pharmacology and to validate the importance of this neurocircuitry in animal models. Although there is prior art, no small molecule has yet demonstrated robust in vivo efficacy in multiple animal models. The present report discloses the discovery and characterization of a potent NPSR antagonist having an imidazo-pyridinium molecular core and an unusual, yet stable phosphorothioyl species. The probe molecule is the most potent compound yet reported and has promising microsomal stability compared to other lead NPSR antagonists disclosed in the literature. In vivo rodent pharmacokinetic experiments show that a 10 mpk dose administered IP may provide sufficient exposure in brain to see functional antagonism for many hours. The probe completely antagonizes NPS activation of the NPS/NPSR neurocircuitry in a food intake rat model using intracerebroventricular (icv) administration.

ML154

Key Investigators

National Center for Advancing Translational Sciences
Samarjit Patnaik, Ph.D.
Juan Marugan, Ph.D.
Ke Liu, Ph.D.
Wei Zheng, Ph.D.
Noel Southall, Ph.D.
James Inglese, Ph.D.
Christopher Austin, M.D.

National Institute on Alcohol Abuse and Alcoholism
Annika Thorsell, Ph.D.
Robert Eskay, Ph.D.
Markus Heilig, M.D., Ph.D.

Public Health Impact

This probe compound can be used as a tool molecule by biologists interested in understanding NPS/NPSR pharmacology and the role of NPSR antagonism in sleep, anxiety, food intake, and addiction.

Publications

Kallupi M, Cannella N, Economidou D, et al. Physiopathological role of the neuropeptide S system in cocaine relapse: A mechanism mediated by the hypothalamic hypocretin system. PNAS, 2010;107(45):19567-19572.

Liu K, Southall N, Titus SA, et al. A multiplex calcium assay for identification of GPCR agonists and antagonists. Assay Drug Dev Technol, 2010;8:367-379.

McCoy JG, Marugan JJ, Liu K, et al. Selective modulation of Gq/Gs pathways by naphtho pyrano pyrimidines as antagonists of the neuropeptide S receptor. ACS Chem Neurosci, 2010;1:559-574.

Probe Report

Identification of Novel Small Molecule Antagonists of the Neuropeptide-S Receptor