The development of nonpeptide systemically active small-molecule NOP-targeted ligands has contributed tremendously to validating the NOP receptor as a promising target for therapeutics. Although a NOP-targeted compound is not yet approved for clinical use, a few NOP ligands are in clinical trials for various indications. Both successful and failed human clinical trials with NOP ligands provide opportunities for rational development of new and improved NOP-targeted compounds. A few years after the discovery of the NOP receptor in 1994, and its de-orphanization upon discovery of the endogenous peptide nociceptin/orphanin FQ (N/OFQ) in 1995, there was a significant effort in the pharmaceutical industry to discover nonpeptide NOP ligands from hits obtained from high-throughput screening campaigns of compound libraries. Depending on the therapeutic indication to be pursued, NOP agonists and antagonists were discovered, and some were optimized as clinical candidates. Advances such as G protein-coupled receptor (GPCR) structure elucidation, functional selectivity in ligand-driven GPCR activation, and multi-targeted ligands provide new scope for the rational design of novel NOP ligands fine-tuned for successful clinical translation. This article reviews the field of nonpeptide NOP ligand drug design in the context of these exciting developments and highlights new optimized nonpeptide NOP ligands possessing interesting functional profiles, which are particularly attractive for several unmet clinical applications involving NOP receptor pharmacomodulation.
Keywords: NOP agonists; NOP antagonists; NOP ligands; Nociceptin ligands; Small-molecule NOP ligands.