Identification of novel Neuropeptide S receptor ligands as treatments for substance abuse.

S.P. Runyon2, C Hassler2, N Goeders1, C Schmoutz1, R Reinscheid3. 1LSU, Pharmacology and Toxicology, USA, 2Research Triangle Institute, Organic and Medicinal Chemistry, USA, 3UC Irvine, Pharmacology, USA

The coupling of putative neurotransmitters with orphan receptors using reverse pharmacology has led to the identification of several important ligand-receptor associations that are beginning to demonstrate novel pharmacology in vivo. In particular, this technique has led to the pairing of neuropeptide S (NPS) with its cognate G-protein coupled receptor (NPSR). Neuropeptide S is a 20-amino acid peptide that functions as an agonist through activation of its cognate GPCR receptor system. Modulation of the Neuropeptide S (NPS) receptor has been associated with a variety of disease states including anxiety, panic disorder, narcolepsy, PTSD, and importantly substance abuse. Our program has been focused on developing novel chemical entities based on the bicyclic piperazine scaffold (SHA-68) that suffers from poor drug-like properties and primarily poor aqueous solubility. Through comprehensive chemical modification and analog synthesis we have now defined a comprehensive NPS antagonist pharmacophore using traditional medicinal chemistry and computational/scaffold hopping approaches. The compounds developed in our laboratory are highly potent (Ke = 15 nM) at blocking the human and mouse NPS receptor in vitro using a calcium mobilization functional assay and are also active in rodent models of cocaine self-administration, stress induced, cue induced, and drug induced reinstatement. Cocaine self administration responses were reduced 60%, cue induced reinstatement was reduced 65%, stress induced reinstatement was reduced 65%, and cocaine induced reinstatement was reduced 55% over vehicle controls at 20 mg/kg ip. of RTI-118. Our program has been focused primarily on modification of the bicyclic core scaffold of SHA-68 through the synthesis various N-substituted analogs and modification of the diaryl core. Further modification and testing of these analogs will be of significant value in determining the comprehensive role of NPS in modulating substance abuse behaviors.