Efficient design, synthesis and structure–activity relationship studies of 1-(3′-substituted propyl)-4-arylpiperidines as non-peptide antagonists of nociceptin/orphanin FQ receptor: biological activities, metabolic stabilities and hERG channel bindings

Abstract

Nociceptin/orphanin FQ (N/OFQ) is an endogenous heptadecapeptide that is a metabolite of precursor polypeptide (prepro-N/OFQ), and N/OFQ peptide (NOP) receptor (or opioid-receptor-like-1 receptor) is a G-protein-coupled receptor (GPCR) that is distinct from classical opioid peptide receptors, whereas the receptors share high sequence-similarities. As well, [35S]-guanosine 5′-(γ-thiotriphosphate) binding that was stimulated by N/OFQ–NOP receptor binding was not affected by various GPCR antagonists including opioid receptor antagonists. N/OFQ and NOP receptor are located in the spinal cord, the peripheral nervous systems and other peripheral tissues that are related to pain-inhibitory signal transmissions, and in the corticolimbic regions that are involved in the integration of the emotional components. Indeed, potent and selective new-class NOP receptor agonists as systemically potent analgesic against neuropathic pain and as orally potent anxiolytic with respective unique safe-profiles have been discovered in our studies. Besides, the blockade of N/OFQ actions via N/OFQ–NOP receptor system has been displayed as anti-depression effect, anti-hyperphasia effect and anti-hypotension effect in animal model studies, which might show potential utilities of NOP receptor antagonists to modulate/attenuate N/OFQ activity for regulation of human physiologies in pharmacological and clinical viewpoints. Hence, the design, synthesis, structure–activity relationship in vitro and structure–metabolic stability relationship in vitro of various 1-(3′-substituted propyl)-4-arylpiperidine derivatives were investigated to seek and identify potent and selective new-class NOP receptor antagonists with metabolic stabilities and little hERG ion channel binding affinities by multi-viewpoint and integrated drug-design strategies, with clarifying structural features and physicochemical properties as key factors for the purposes. The unique and efficient studies, and their exclusive results and findings for the analogues are described herein. Efficient and novel methodology of multi-analogue synthesis for 1-[3′-(N,N-disubstituted amino)propyl]-4-arylpiperidine derivatives 3.