In vitro and in vivo activity of cyclopeptide Dmt-c[ d -Lys-Phe-Asp]NH 2 , a mu opioid receptor agonist biased toward β-arrestin

Opioids reduce the cholinergic responses to electrical field stimulation (EFS) in guinea pig and canine airways by a prejunctional effect. We determined whether a similar effect operates in human airways in vitro. [D-Ala2-NMePhe4-Gly-ol5]enkephalin (DAMGO) (10(-8)-10(-6) M), a selective mu-opioid receptor agonist, inhibited the response to EFS in a dose- and frequency-dependent manner. DAMGO (10(-6) M) produced 86% inhibition at 0.5 Hz and 38% inhibition at 4 Hz, but at 32 Hz there was no significant inhibition. Another selective mu-opioid receptor agonist H-Tyr-D-Arg-Gly-Phe(4-NO2)-Pro-NH2 diacetate (BW 443C) also inhibited responses to EFS, producing 57.7% inhibition at 4 Hz at a concentration of 10(-6) M. The inhibitory effect on EFS was blocked by the opioid receptor antagonist naloxone (10(-5) M), indicating that opioid receptors are involved. DAMGO (10(-6) M) had no effect on the contractile response to exogenous acetylcholine, indicating a prejunctional effect. We conclude that mu-opioid agonists inhibit cholinergic neurotransmission in human airways in vitro, and this could have therapeutic potential in the treatment of airway disease.

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Faculty Opinions recommendation of Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1086845.539776 ◽

2007 ◽

Author(s):

Howard Fields

Keyword(s):

Receptor Antagonist ◽

Conditioned Place Preference ◽

Opioid Receptor ◽

Receptor Agonist ◽

Mu Opioid Receptor ◽

Place Preference ◽

Delta Opioid Receptor ◽

Bivalent Ligands ◽

Mu Opioid ◽

Opioid Receptor Agonist

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Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma

Life Sciences ◽

10.1016/j.lfs.2021.119541 ◽

2021 ◽

Vol 278 ◽

pp. 119541

Author(s):

Aysegul Gorur ◽

Miguel Patiño ◽

Hideaki Takahashi ◽

German Corrales ◽

Curtis R. Pickering ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Growth ◽

Cell Carcinoma ◽

Head And Neck ◽

Opioid Receptor ◽

Receptor Activation ◽

Mu Opioid Receptor ◽

Mu Opioid

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Receptor Binding Properties and Antinociceptive Effects of Chimeric Peptides Consisting of a μ-Opioid Receptor Agonist and an ORL1 Receptor Antagonist

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.30.1260 ◽

2007 ◽

Vol 30 (7) ◽

pp. 1260-1264 ◽

Cited By ~ 9

Author(s):

Susumu Kawano ◽

Risa Ito ◽

Miharu Nishiyama ◽

Mai Kubo ◽

Tomoko Matsushima ◽

...

Keyword(s):

Receptor Antagonist ◽

Opioid Receptor ◽

Receptor Binding ◽

Receptor Agonist ◽

Mu Opioid Receptor ◽

Binding Properties ◽

Mu Opioid ◽

Opioid Receptor Agonist ◽

Antinociceptive Effects ◽

Chimeric Peptides

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6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

10.26434/chemrxiv.14204834.v1 ◽

2021 ◽

Author(s):

Nicholas S. Akins ◽

Nisha Mishra ◽

Hannah M. Harris ◽

Narendar Dudhipala ◽

Seong Jong Kim ◽

...

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Analgesic Activity ◽

Mu Opioid Receptor ◽

Kappa Opioid Receptor ◽

Mu Opioid ◽

Receptor Agonists ◽

Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. In vivo studies on the lead dual kappa and mu opioid receptor agonist, compound 10, showed that it produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

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