Discovery of 1-(β-amino substituted-β-alanyl)-N,N-dimethylindoline-2-carboxamides as novel nonpeptide antagonists of nociceptin/orphanin FQ receptor: Efficient design, synthesis, and structure–activity relationship studies

Since the discovery of endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor], the structures, distribution, and pharmacology have been reported in detail. N/OFQ and NOP receptor are located in the corticolimbic regions that are involved in the integration of the emotional activity, and located in the spinal cord, the peripheral nervous systems or other peripheral tissues that are related to pain as well as urinary signal transmissions, with a pattern distinct from that of classical opioid peptides and their receptors in rodents or primates. Furthermore, N/OFQ–NOP receptor system plays an important role in the regulation of various human physiologies such as depression effect, hyperphasia effect, and blood pressure effect. In this study, the structure–activity relationship of novel NOP receptor antagonist for various 1-(β-amino substituted-β-alanyl)-N,N-dimethylindoline-2-carboxamides was investigated in vitro to elucidate structural requisites to identify and develop potent and selective NOP receptor antagonists, which resulted in the discovery of 1-{3-[4-(substituted phenyl)piperidin-1-yl]propanoyl}-N,N-dimethylindoline-2-carboxamide analogues that display potent and selective human NOP (hNOP) receptor binding affinity and potent hNOP receptor antagonist activity. The efficient design, synthesis, and structure–activity relationship studies for potent and selective novel NOP receptor antagonists and significant findings in vitro, that include insights for binding and functional mechanisms via receptor–ligand interactions, are reported herein.

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► Various β-alanine derivatives were efficiently designed and synthesized.
► 4-Phenylpiperidine analogues were identified as novel hNOP receptor antagonists.
► Compound 7d exhibited promising profile in SAR and SMR studies in vitro.
► The requisites for potency, selectivity, and metabolic stability were elucidated.