Small Molecule Neuropeptide S and Melanocortin 4 Receptor Ligands as Potential Treatments for Substance Use Disorders

There is a vital need for novel approaches and biological targets for drug discovery and development. Treatment strategies for substance use disorders (SUDs) to date have been mostly ineffective other than substitution-like therapeutics. Two such targets are the peptide G-protein-coupled receptors neuropeptide S (NPS) and melanocortin 4 (MC4). Preclinical evidence suggests that antagonists, inverse agonists, or negative allosteric modulators of these receptors might be novel therapeutics for SUDs. NPS is a relatively unexplored receptor with high potential for treating SUD. MC4 has a strong link to early-onset obesity, and emerging evidence suggests significant overlap between food-maintained and drug-maintained behaviors making MC4 an intriguing target for SUD. This chapter provides an overview of the literature in relation to the roles of NPS and MC4 in drug-seeking behaviors and then provides a medicinal chemistry-based survey of the small molecule ligands for each receptor.