nor-Binaltorphimine dihydrochloride

Perivascular expression and potent vasoconstrictor effect of dynorphin A in cerebral arteries.[Pubmed:22662226]

PLoS One. 2012;7(5):e37798.

BACKGROUND: Numerous literary data indicate that dynorphin A (DYN-A) has a significant impact on cerebral circulation, especially under pathophysiological conditions, but its potential direct influence on the tone of cerebral vessels is obscure. The aim of the present study was threefold: 1) to clarify if DYN-A is present in cerebral vessels, 2) to determine if it exerts any direct effect on cerebrovascular tone, and if so, 3) to analyze the role of kappa-opiate receptors in mediating the effect. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical analysis revealed the expression of DYN-A in perivascular nerves of rat pial arteries as well as in both rat and human intraparenchymal vessels of the cerebral cortex. In isolated rat basilar and middle cerebral arteries (BAs and MCAs) DYN-A (1-13) and DYN-A (1-17) but not DYN-A (1-8) or dynorphin B (DYN-B) induced strong vasoconstriction in micromolar concentrations. The maximal effects, compared to a reference contraction induced by 124 mM K(+), were 115+/-6% and 104+/-10% in BAs and 113+/-3% and 125+/-9% in MCAs for 10 microM of DYN-A (1-13) and DYN-A (1-17), respectively. The vasoconstrictor effects of DYN-A (1-13) could be inhibited but not abolished by both the kappa-opiate receptor antagonist nor-Binaltorphimine dihydrochloride (NORBI) and blockade of G(i/o)-protein mediated signaling by pertussis toxin. Finally, des-Tyr(1) DYN-A (2-13), which reportedly fails to activate kappa-opiate receptors, induced vasoconstriction of 45+/-11% in BAs and 50+/-5% in MCAs at 10 microM, which effects were resistant to NORBI. CONCLUSION/SIGNIFICANCE: DYN-A is present in rat and human cerebral perivascular nerves and induces sustained contraction of rat cerebral arteries. This vasoconstrictor effect is only partly mediated by kappa-opiate receptors and heterotrimeric G(i/o)-proteins. To our knowledge our present findings are the first to indicate that DYN-A has a direct cerebral vasoconstrictor effect and that a dynorphin-induced vascular action may be, at least in part, independent of kappa-opiate receptors.

Differential agonist regulation of the human kappa-opioid receptor.[Pubmed:9109509]

J Neurochem. 1997 May;68(5):1846-52.

Opiates are potent analgesics used clinically in the treatment of pain. A significant drawback to the chronic use and clinical effectiveness of opiates is the development of tolerance. To investigate the cellular mechanisms of tolerance, the cloned human kappa-opioid receptor was stably expressed in human embryonic kidney (HEK 293) cells, and the effects of opioid agonist treatment were examined. The receptor-expressing cells showed specific high-affinity membrane binding for a kappa-selective opioid, 3H-labeled (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiny l)-1-oxaspiro [4,5] dec-8-yl] benzeneacetamide ([3H]U69,593), and a nonselective opioid antagonist, [3H]diprenorphine. Pretreatment with pertussis toxin or guanosine 5'-O-(3-thiotriphosphate) reduced [3H]69,593 binding, indicating that the human K receptor coupled to G proteins of the Gi or Go families in HEK 293 cells. The receptor-mediated inhibition of adenylyl cyclase was abolished by pertussis toxin pretreatment and was blocked by a kappa-selective antagonist, norbinaltorphimine. A 3-h pretreatment with a kappa-selective agonist, (+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide (U50,488), caused receptor down-regulation, whereas no receptor down-regulation was found after levorphanol pretreatment. U50,488 or dynorphin A(1-17) pretreatments (3 h) desensitized the ability of U50,488 or dynorphin A(1-17) to inhibit cyclic AMP accumulation, as evidenced by a decrease in functional potency. Also, U50,488 pretreatment desensitized the ability of levorphanol to inhibit forskolin-stimulated cyclic AMP accumulation. In contrast, pretreatment of cells with either levorphanol or a potent nonselective opioid, etorphine, resulted in no apparent receptor desensitization. Taken together, these results demonstrate that the human kappa receptor is differentially regulated by selective and nonselective opioid agonists, with selective agonists able to desensitize the receptor.

Nor-binaltorphimine precipitates withdrawal and excitatory amino acid release in the locus ceruleus of butorphanol--but not morphine-dependent rats.[Pubmed:9353416]

J Pharmacol Exp Ther. 1997 Nov;283(2):932-8.

The relative involvement of kappa opioid receptors in the mediation of behavioral and neurochemical responses to withdrawal from chronic drug treatment with the opioid analgesic butorphanol was studied using in vivo microdialysis to detail extracellular fluid concentrations of glutamate and aspartate within the locus ceruleus. Sprague-Dawley rats were rendered opioid dependent after 3 days of intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/microl/hr) or morphine (26 nmol/microl/hr) and after i.c.v. infusion of saline vehicle (1 microl/hr). Acute withdrawal was precipitated by i.c.v. injection of the selective kappa opioid receptor antagonist nor-binaltorphimine (48 nmol/5 microl) after the 3-day period of infusion. Behavioral signs of withdrawal were detected after nor-binaltorphimine only in butorphanol-dependent rats. Basal levels of glutamate and aspartate were not different between treatment groups. Nor-binaltorphimine in the butorphanol-dependent rats increased glutamate to 227% and aspartate to 158% in the initial 15-min sample (P < 0.01). Nor-binaltorphimine did not increase glutamate or aspartate concentrations in the morphine-dependent or saline-treated groups. These results indicate a significantly greater participation of kappa opioid receptors in the development of butorphanol, rather than morphine, dependence and identify a differential neurochemical response to butorphanol withdrawal within a defined brain region, the locus ceruleus.

Structure-activity relationship of N17'-substituted norbinaltorphimine congeners. Role of the N17' basic group in the interaction with a putative address subsite on the kappa opioid receptor.[Pubmed:8182708]

J Med Chem. 1994 May 13;37(10):1495-500.

A series of norbinaltorphimine congeners (2-12) which contain different groups at the N17'-position have been synthesized in order to evaluate the role of N17' in conferring kappa opioid antagonist selectivity at opioid receptor sites. The compounds that contain a basic N17' nitrogen (2-9) were found to be selective kappa antagonists. Amidation of N17' afforded congeners 10-12 with feeble kappa antagonist potency and low selectivity. The fact that potent antagonism and selectivity were observed only when members of the series contain a basic N17' nitrogen suggests that it interacts with extracellular domains of the kappa receptor that contain acidic amino acid residues. The N-terminal domain and extracellular loop 2, both of which contain acidic residues, are candidates for this interaction and may be components of the kappa address subsite of the receptor.