Different domains of the ORL1 and κ-opioid receptors are involved in recognition of nociceptin and dynorphin A

The opioid binding profile and in vitro activity of the endogenous opioid peptide dynorphin A(1-8) have been studied. At opioid receptors in guinea-pig brain dynorphin A(1-8) was nonselective, although with some preference for the delta receptor (Ki 4.6 nM) over µ (Ki 18 nM) and kappa (Ki 40 nM) receptors. However, a high degree of metabolism was observed, with less than 10% of added dynorphin A(1-8) remaining at the end of the binding assay. In the presence of peptidase inhibitors to prevent breakdown of the N- and C-termini and the Gly3-Phe4 bond the major metabolite was [Leu5]enkephalin (representing 49% recovered material). This was reduced by inclusion of an inhibitor of endopeptidase EC 3.4.24.15. In the presence of all the peptidase inhibitors the affinity for kappa receptors (Ki 0.5 nM) relative to µ and delta receptors increased, but no selectivity of binding was observed. This lack of selectivity was confirmed using membranes from C6 glioma cells expressing rat opioid receptors. The agonist effect of dynorphin A(1-8) in the mouse vas deferens (EC50 116 nM) and guinea-pig ileum (EC50 38 nM) was mediated through the kappa receptor as evidenced by the rightward shifts afforded by the kappa -selective antagonist norbinaltorphimine. In the presence of peptidase inhibition potency was improved 2-fold in the mouse vas deferens and 20-fold in the guinea-pig ileum, but this agonist activity was mediated through delta receptors in the vas deferens and µ receptors in the ileum, as a result of the formation and stabilization of [Leu5]enkephalin. The results confirm the absence of receptor selectivity of dynorphin A(1-8) in binding assays but show that its agonist effects, at least in vitro, are mediated exclusively through the kappa opioid receptor.Key words: dynorphin A(1-8), opioid receptors, peptide metabolism, mouse vas deferens, guinea-pig ileum.

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Selective inactivation of opioid receptors in rat hippocampus demonstrates that dynorphin-A and -B may act on μ-receptors in the CA1 region

Brain Research ◽

10.1016/0006-8993(85)91565-3 ◽

1985 ◽

Vol 331 (2) ◽

pp. 366-370 ◽

Cited By ~ 37

Author(s):

C. Chavkin ◽

S.J. Henriksen ◽

G.R. Siggins ◽

F.E. Bloom

Keyword(s):

Opioid Receptors ◽

Rat Hippocampus ◽

Dynorphin A ◽

Ca1 Region

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Autoradiographic localization of supraspinal kappa-opioid receptors with [125I-Tyr1, D-Pro10]dynorphin A-(1-11).

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.85.2.627 ◽

1988 ◽

Vol 85 (2) ◽

pp. 627-631 ◽

Cited By ~ 9

Author(s):

C. Jomary ◽

J. E. Gairin ◽

J. Cros ◽

J. C. Meunier

Keyword(s):

Opioid Receptors ◽

Kappa Opioid Receptors ◽

Dynorphin A ◽

Kappa Opioid

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N-Terminal alkylated derivatives of [D-Pro10]dynorphin A-(1-11) are highly selective for .kappa.-opioid receptors

Journal of Medicinal Chemistry ◽

10.1021/jm00102a019 ◽

1992 ◽

Vol 35 (24) ◽

pp. 4638-4639 ◽

Cited By ~ 18

Author(s):

Heekyung Choi ◽

Thomas F. Murray ◽

Gary E. DeLander ◽

Valerie Caldwell ◽

Jane V. Aldrich

Keyword(s):

Opioid Receptors ◽

Kappa Opioid Receptors ◽

Dynorphin A ◽

Kappa Opioid ◽

Derivatives Of

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Opioid receptors in GtoPdb v.2021.3

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f50/2021.3 ◽

2021 ◽

Vol 2021 (3) ◽

Author(s):

Anna Borsodi ◽

Michael Bruchas ◽

Girolamo Caló ◽

Charles Chavkin ◽

MacDonald J. Christie ◽

...

Keyword(s):

Opioid Receptors ◽

Opioid Analgesics ◽

Structural Homology ◽

Orphanin Fq ◽

Dynorphin A ◽

Greek Letter ◽

Endogenous Peptides ◽

High Degree ◽

Μ Receptor

Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [121, 100, 91]. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [294], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone, however only for the μ receptor.

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Distinct Mechanisms for Activation of the Opioid Receptor-Like 1 and κ-Opioid Receptors by Nociceptin and Dynorphin A

Molecular Pharmacology ◽

10.1124/mol.55.2.324 ◽

1999 ◽

Vol 55 (2) ◽

pp. 324-331 ◽

Cited By ~ 65

Author(s):

Catherine Mollereau ◽

Lionel Mouledous ◽

Sophie Lapalu ◽

Gilles Cambois ◽

Christiane Moisand ◽

...

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Dynorphin A

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Opioid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f50/2019.4 ◽

2019 ◽

Vol 2019 (4) ◽

Cited By ~ 2

Author(s):

Anna Borsodi ◽

Michael Bruchas ◽

Girolamo Caló ◽

Charles Chavkin ◽

MacDonald J. Christie ◽

...

Keyword(s):

Opioid Receptors ◽

Opioid Analgesics ◽

Structural Homology ◽

Orphanin Fq ◽

Dynorphin A ◽

Greek Letter ◽

Endogenous Peptides ◽

High Degree ◽

Μ Receptor

Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [116, 96, 88]. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [282], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone, however only for the μ receptor.

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