Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys

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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Interactions Between Mu Opioid Receptor Agonists in Rats Discriminating Fentanyl

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.04294 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Shawn Flynn ◽

Charles France

Keyword(s):

Opioid Receptor ◽

Mu Opioid Receptor ◽

Mu Opioid ◽

Receptor Agonists ◽

Opioid Receptor Agonists

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The Endogenous Mu-Opioid Receptor Agonists Endomorphins 1 and 2 Have Novel Hypotensive Activity in the Rabbit

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1997.6843 ◽

1997 ◽

Vol 235 (3) ◽

pp. 567-570 ◽

Cited By ~ 51

Author(s):

Hunter C. Champion ◽

James E. Zadina ◽

Abba J. Kastin ◽

Laszlo Hackler ◽

Lin-Jun Ge ◽

...

Keyword(s):

Opioid Receptor ◽

Mu Opioid Receptor ◽

Hypotensive Activity ◽

Mu Opioid ◽

Receptor Agonists ◽

Opioid Receptor Agonists

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Discovery of Biased Mu‐Opioid Receptor Agonists for the Treatment of Pain

ChemMedChem ◽

10.1002/cmdc.201900575 ◽

2019 ◽

Vol 15 (1) ◽

pp. 155-161 ◽

Cited By ~ 2

Author(s):

Mengjun Ma ◽

Xiang Li ◽

Kun Tong ◽

Jingchao Cheng ◽

Zixing Yu ◽

...

Keyword(s):

Opioid Receptor ◽

Mu Opioid Receptor ◽

Mu Opioid ◽

Receptor Agonists ◽

Opioid Receptor Agonists

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Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach

Pain Medicine ◽

10.1093/pm/pnz122 ◽

2019 ◽

Vol 21 (5) ◽

pp. 992-1004 ◽

Cited By ~ 2

Author(s):

Lynn Webster ◽

William K Schmidt

Keyword(s):

Side Effects ◽

Respiratory Depression ◽

Opioid Receptor ◽

Severe Pain ◽

Mu Opioid Receptor ◽

Endogenous Opioid Peptides ◽

Endogenous Opioid ◽

Mu Opioid ◽

Receptor Agonists ◽

Opioid Receptor Agonists

Abstract Objective Although mu-opioid receptor agonists have been the mainstay of analgesic regimens for moderate to severe pain, they are associated with serious side effects, risks, and limitations. We evaluate the most serious risks associated with conventional opioids and compare these with the pharmacology of CYT-1010, a prototypical endomorphin and mu-opioid receptor agonist. Results Addiction and respiratory depression are serious risks of traditional mu-opioid analgesics. Mitigation strategies have been inadequate at addressing the opioid crisis and may interfere with the effective treatment of pain. Improved understanding of mu-opioid receptor biology and the discovery in 1997 of an additional and unique family of endogenous opioid peptides (endomorphins) have provided a pathway for dissociating analgesia from opioid-related adverse events and developing new classes of mu-opioid receptor agonists that use biased signaling and/or target novel sites to produce analgesia with reduced side effect liability. Endomorphin-1 and -2 are endogenous opioid peptides highly selective for mu-opioid receptors that exhibit potent analgesia with reduced side effects. CYT-1010 is a cyclized, D-lysine-containing analog of endomorphin-1 with a novel mechanism of action targeting traditional mu- and exon 11/truncated mu-opioid receptor 6TM variants. CYT-1010 preclinical data have demonstrated reduced abuse potential and analgesic potency exceeding that of morphine. In an initial phase 1 clinical study, CYT-1010 demonstrated significant analgesia vs baseline and no respiratory depression at the dose levels tested. Conclusions CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain.

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