Nociceptin, an endogenous ligand for the ORL1 receptor, has novel hypotensive activity in the rat

doi:10.1016/S0024-3205(97)00087-8

Life Sciences

Volume 60, Issue 16, 14 March 1997, Pages PL241-PL245

https://doi.org/10.1016/S0024-3205(97)00087-8 Get rights and content

Abstract

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein coupled receptor, ORL₁. In the present study responses to intravenous administration of nociceptin were investigated in the systemic vascular bed of the rat. Nociceptin induced dose-related decreases in systemic arterial pressure when injected in doses of 1–30 $nmol kg$ i.v. In tarns of relative vasodepressor activity, nociceptin was approximately 10-fold more potent than the nitric oxide donor, DEA/NO, and 10-fold less potent than adrenomedullin. The duration of the vasodepressor response to nociceptin was shorter than adrenomedullin but longer than DEA/NO. These results show that nociceptin has significant vasodepressor activity in the rat.

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Cited by (95)

Therapeutic potential of nociceptin/orphanin FQ peptide (NOP) receptor modulators for treatment of traumatic brain injury, traumatic stress, and their co-morbidities
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The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is a member of the opioid receptor superfamily with N/OFQ as its endogenous agonist. Wide expression of the NOP receptor and N/OFQ, both centrally and peripherally, and their ability to modulate several biological functions has led to development of NOP receptor modulators by pharmaceutical companies as therapeutics, based upon their efficacy in preclinical models of pain, anxiety, depression, Parkinson’s disease, and substance abuse. Both posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are debilitating conditions that significantly affect the quality of life of millions of people around the world. PTSD is often a consequence of TBI, and, especially for those deployed to, working and/or living in a war zone or are first responders, they are comorbid. PTSD and TBI share common symptoms, and negatively influence outcomes as comorbidities of the other. Unfortunately, a lack of effective therapies or therapeutic agents limits the long term quality of life for either TBI or PTSD patients. Ours, and other groups, demonstrated that PTSD and TBI preclinical models elicit changes in the N/OFQ-NOP receptor system, and that administration of NOP receptor ligands alleviated some of the neurobiological and behavioral changes induced by brain injury and/or traumatic stress exposure. Here we review the past and most recent progress on understanding the role of the N/OFQ-NOP receptor system in PTSD and TBI neurological and behavioral sequelae. There is still more to understand about this neuropeptide system in both PTSD and TBI, but current findings warrant further examination of the potential utility of NOP modulators as therapeutics for these disorders and their co-morbidities. We advocate the development of standards for common data elements (CDE) reporting for preclinical PTSD studies, similar to current preclinical TBI CDEs. That would provide for more standardized data collection and reporting to improve reproducibility, interpretation and data sharing across studies.
Plasma nociceptin/orphanin FQ levels are lower in patients with chronic ischemic cardiovascular diseases-A pilot study
2011, Regulatory Peptides
Citation Excerpt :
The role of N/OFQ in the cardiovascular system was demonstrated in a large number of experimental studies. Based on in vitro and in vivo results it is generally accepted that N/OFQ induces hypotension, bradycardia and vasodilation by influencing the central nervous system and peripheral tissues both directly and indirectly by reducing sympathetic and increasing parasympathetic influence on neurons innervating the heart and the vascular system [7–10,16–18,25,27,29,32] These findings were also confirmed in a study with spontaneously hypertensive rats [26], as well as in rats on chronic high-NaCl-diet, whereas prolonged effects have been seen after the administration of N/OFQ [41]. In an experimental model cerebrospinal fluid (CSF) nociceptin/orphanin FQ was found elevated after acute cerebral ischemia–reperfusion (I/R) and combined hypoxia and ischemia–reperfusion (H–I/R) injury, whereas values returned to control level within a few hours of reperfusion [3].
Clinical studies are limited regarding the role of human nociceptin/orphanin FQ (N/OFQ) in ischemic cardiovascular diseases, which are still the number one cause of death in the developed world. The aim of our study was to measure the plasma levels of N/OFQ in patients with chronic ischemic cardiovascular diseases in a pilot study.
Our study population consisted of 22 patients presenting symptoms of stable angina pectoris (SAP): 12 severe Canadian Cardiovascular Society (CCS) III–IV functional class, and 10 with milder SAP (CCS II–III). 12 patients were also enrolled with chronic peripheral artery disease (9 with intermittent claudication; 3 with rest pain and gangrene). Patients were asked to avoid any exertion or given analgetics for their rest pain. Patients had no episodes of chest or limb pain in 1 week before their fasting blood samples were taken and N/OFQ plasma levels were measured by radioimmunoassay. 14 healthy subjects without any cardiac risk factors served as a control group.
N/OFQ levels were significantly lower in patient groups with severe vs. milder chronic angina (p < 0.05) and vs. control subjects (p < 0.01). Patients suffering from peripheral artery disease had also a lower plasma N/OFQ levels than in healthy controls (p < 0.01). Our findings show that chronic ischemic conditions of atherosclerotic origin are associated with significantly lower plasma N/OFQ levels.
Efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate, a useful intermediate for the synthesis of nociceptin antagonists
2009, Tetrahedron Asymmetry
An efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate 1, a useful intermediate for the synthesis of nociceptin antagonists, has been developed. This method includes the following key steps: (1) diastereoselective reduction of a chiral enaminoester 3 having (R)-1-phenylethylamine as a chiral pool constituent with the use of a combined TFA–NaBH₄ reduction system and (2) efficient isomerization from 3,4-cis-substituted piperidine 8 to 3,4-trans-substituted piperidine 1 under basic conditions. The above methods proved to be applicable for large-scale operation and hundred grams of enantiomerically pure compound 1 (>98% ee) was obtained.
Identification of MK-1925: A selective, orally active and brain-penetrable opioid receptor-like 1 (ORL1) antagonist
2009, Bioorganic and Medicinal Chemistry Letters
Structure–activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.
Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists
2009, Bioorganic and Medicinal Chemistry Letters
The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure–activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.
2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists
2009, Bioorganic and Medicinal Chemistry Letters
The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.

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Pharmacology letter Accelerated communicationNociceptin, an endogenous ligand for the ORL1 receptor, has novel hypotensive activity in the rat

Abstract

FEES Lett.

FEBS Lett.

Biochem. Biophys. Res. Commun.

FEBS Lett.

FEBS Lett.

FEBS Lett.

Mol. Brain Res.

J. Neuroimmunol.

Pharmacology letter Accelerated communication
Nociceptin, an endogenous ligand for the ORL₁ receptor, has novel hypotensive activity in the rat