Evidence that endogenous 6-(Arg or Lys)-opioid peptides can interact with κ-receptors as agonists

Oka, Tetsuo; Negishi, Kazuko

doi:10.1016/0024-3205(82)90191-6

Cited by 17 publications

(8 citation statements)

References 12 publications

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“…Interestingly, the ability of dyn-(1-17) to act as a µ-agonist has recently been shown by using membranes from C 6 rat glioma cells expressing a cloned rat µ-receptor (Alt et al 1998) and from AV12 cells expressing the cloned human µ-receptor (Zhang et al 1998). Although the ability of dyn-(1-8) to act as a µ-agonist has not been tested in both studies, these experiments indicate the possibility that dyn-(1-8) also has an ability to act as a µ-agonist, since dyn-(1-8) is generally thought to have a similar property as dyn-(1-17) in terms of a preference for opioid-receptor types (Corbett et al 1982;Oka and Negishi 1982;Yoshino et al 1990). …”

Section: Discussionmentioning

confidence: 89%

“…As far as we know, the evidence that dyn-(1-8) acts as a µ-agonist in isolated preparations such as guinea-pig ileum and mouse vas deferens has not been reported although it is well-known to act as a potent κ-agonist in these preparations (Corbett et al 1982;Oka and Negishi 1982;Numata et al 1988;Hiranuma et al 1998). Interestingly, the ability of dyn-(1-17) to act as a µ-agonist has recently been shown by using membranes from C 6 rat glioma cells expressing a cloned rat µ-receptor (Alt et al 1998) and from AV12 cells expressing the cloned human µ-receptor (Zhang et al 1998).…”

Section: Discussionmentioning

confidence: 94%

“…In fact, the potency of dyn-(1-8) in guinea-pig ileum has been shown to be significantly increased by either amastatin or phosphoramidon (Numata et al 1988). In contrast to the hydrolysis products of dyn-(1-8) by AsA and PsE, [Leu 5 ]-enkephalinArg 6 , the initial major hydrolysis product of dyn-(1-8) by CsD, still has the high agonist activity at µ-opioid receptors in guinea-pig ileum and at the δ-receptors in mouse vas deferens (Hiranuma et al 1998), although dyn-(1-8) itself is well-known to act as a potent κ-agonist in both preparations (Corbett et al 1982;Oka and Negishi 1982). This indicates that dyn-(1-8) itself or its initial main hydrolysis product, [Leu 5 ]-enkephalin-Arg 6 , acts at either κ-, µ-or δ-opioid receptors, depending on both the relative activity of the three peptidases, AsA, CsD and PsE, and the relative density of the three opioid-receptor types, κ, µ and δ, in the preparation examined.…”

Section: Introductionmentioning

confidence: 97%

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Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1–8) in rats

Kitamura

Akahori

Yano

et al. 2000

Naunyn-Schmiedeberg's Arch Pharmacol

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Previous in vitro studies showed that the degradation of dynorphin-(1-8) [dyn-(1-8)] by cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon. In the present investigations, effects of the three PIs on the anti-nociception induced by the intra-third-ventricular (i.t.v.) administration of dyn-(1-8) were examined. The inhibitory effect of dyn-(1-8) on the tail-flick response was increased more than 100-fold by the i.t.v. pretreatment of rats with the three PIs. The inhibition produced by dyn-(1-8) in rats pretreated with any combination of two PIs was significantly smaller than that in rats pretreated with three PIs, indicating that any residual single peptidase could inactivate significant amounts of dyn-(1-8). The antagonistic effectiveness of naloxone, a relatively selective mu-opioid antagonist, indicates that dyn-(1-8)-induced inhibition of tail-flick response in rats pretreated with three PIs is mediated by mu-opioid receptors. Furthermore, mu-receptor-mediated inhibition induced by dyn-(1-8) was significantly greater than that produced by [Met5]-enkephalin in rats pretreated with three PIs. The data obtained in the present investigations together with those obtained in previous studies strongly indicate that dyn-(1-8) not only has well-known kappa-agonist activity but also has high mu-agonist activity.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 97%

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Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1–8) in rats

Kitamura

Akahori

Yano

et al. 2000

Naunyn-Schmiedeberg's Arch Pharmacol

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Section: Introductionmentioning

confidence: 99%

“…Dyn A mediates an inhibitory effect through the opioid receptors resulting in nociception. Some have studied the importance of consecutive polar residues as is found in Dyn A and found that these were important for binding and function [3].Dyn A has been extensively studied in the search for KOR ligands. Our approach is different in that our main target is a shorter peptide with an amino acid residue deletion in the middle of the sequence.…”

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confidence: 99%

Structure-Activity Relationship Studies of Dynorphin A Analogs at the Kappa Opioid Receptor

Colón¹,

Lee²,

Hall³

et al. 2015

Peptides 2015, Proceedings of the 24th American Peptide Symposium

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IntroductionChronic pain is the most ubiquitous disease with an incidence of 100 million people in the U.S. Opiate therapy is the mainly prescribed treatment for chronic neuropathic pain. However opioids do not address the mechanisms of neuropathic pain and thus have limited efficacy against this type of pain [1]. While opioids may reduce the pain states experienced by the patients, they have adverse effects such as tolerance, addiction, and medication overuse with long-term administration. It has been found that by blocking the κ opioid receptor (KOR) a reduction in tolerance and depressive affective states that can occur with opioid administration [2]. With this in mind we are working towards the development of a KOR selective antagonist with variable duration of action.Dynorphin A (Dyn A, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-AsnGln) is one of three endogenous opioid peptides with high affinities for the μ (MOR), δ (DOR), and κ opioid receptors, with a preference for the KOR. Dyn A mediates an inhibitory effect through the opioid receptors resulting in nociception. Some have studied the importance of consecutive polar residues as is found in Dyn A and found that these were important for binding and function [3].Dyn A has been extensively studied in the search for KOR ligands. Our approach is different in that our main target is a shorter peptide with an amino acid residue deletion in the middle of the sequence. The deleted residue happens to be one of the key residues determined by studies of the relative importance of the amino acid residues in Dyn A sequence. It was previously believed that residues Arg 7 , Lys 11, and Lys 13 were the most important residues for binding and potency at the KOR [4]. The importance of these residues was determined by the binding affinity of truncated analogs of Dyn A. In our approach we are completely deleting the amino acid residue and this is very interesting because usually residue deletions would have unfavorable effects to the binding of a peptide due to changes in conformation and charge distributions. Results and DiscussionDyn A analogs were synthesized by standard solid phase peptide synthesis using Fmoc-chemistry and cleaved by a 95% TFA cocktail solution containing 2.5% TIS, 2.5% water. Crude peptides were purified by RP-HPLC using 10-50% of acetonitrile in water containing 0.1% TFA. Radioligand competition binding assays were done for synthesized analogs using We have identified that Arg 7 is not important nor necessary for binding at KOR as previously believed [4]. We also tested modification of the C-terminal acid to amide (CYF110, CYF111, and CYF112), which showed increased binding affinity at all three opioid receptors. Substitutions of the N-terminal amine group with (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (MDP) or Acetyl (Ac) groups increased KOR selectivity (CYF111, CYF112). It has been previously shown that N-terminal amine substitution of agonist opioid peptides can reverse their functions to antagonists [5].After ...

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The cloned μ, δ and κ receptors and their endogenous ligands: Evidence for two opioid peptide recognition cores

et al. 1995

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Evidence that endogenous 6-(Arg or Lys)-opioid peptides can interact with κ-receptors as agonists

Cited by 17 publications

References 12 publications

Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1–8) in rats

Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1–8) in rats

Structure-Activity Relationship Studies of Dynorphin A Analogs at the Kappa Opioid Receptor

The cloned μ, δ and κ receptors and their endogenous ligands: Evidence for two opioid peptide recognition cores

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