Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin- 1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.

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Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K

Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin- 1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.

Bioorg Med Chem. 2010 Nov 1;18(21):7675-99. doi: 10.1016/j.bmc.2010.07.034. Epub 2010 Jul 21.

PubMed ID
20875743 [ View in PubMed
]
Abstract

Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Adelta-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin- 1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AtenololBeta-1 adrenergic receptorIC 50 (nM)1640N/AN/ADetails
ClorgilineAmine oxidase [flavin-containing] AIC 50 (nM)0.0049N/AN/ADetails
DexamethasoneGlucocorticoid receptorIC 50 (nM)5N/AN/ADetails
EstradiolEstrogen receptor alphaIC 50 (nM)46N/AN/ADetails
ImipramineSodium-dependent serotonin transporterIC 50 (nM)7.3N/AN/ADetails
PirenzepineMuscarinic acetylcholine receptor M1IC 50 (nM)19N/AN/ADetails
ProtriptylineSodium-dependent noradrenaline transporterIC 50 (nM)17N/AN/ADetails
SelegilineAmine oxidase [flavin-containing] BIC 50 (nM)0.017N/AN/ADetails