What question did this study set out to answer?

To synthesize and evaluate indole-diversified mitragynine analogs to explore structure-activity relationships at the mu opioid receptor and identify potent analgesics with attenuated adverse effects.

September 10, 2021Journal of Medicinal ChemistryOpen Access

A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

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Authors

SCSoumen ChakrabortyBiocon (India)JDJeffrey F. DiBertoUniversity of North Carolina at Chapel Hill AFAbdelfattah FaouziUniversity of Health Sciences and Pharmacy

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Implication

Preclinical study demonstrates morphine-like analgesia without respiratory depression or addiction liability in mice, suggesting minimal mu opioid receptor activation can achieve safe pain relief.

Key Points

To synthesize and evaluate indole-diversified mitragynine analogs to explore structure-activity relationships at the mu opioid receptor and identify potent analgesics with attenuated adverse effects.
Synthesized indole-diversified analogs of mitragynine and 7-hydroxymitragynine modified at C9, C10, and C12 positions, identifying three C9-substituted lead compounds.
Profiled mu opioid receptor-mediated G-protein and arrestin signaling using heterologous assays and synaptic physiology, comparing efficacy to DAMGO, morphine, and buprenorphine.
Evaluated lead analog 6 (SC13) in mice for antinociceptive potency, respiratory depression, constipation, hyperlocomotion, and conditioned place preference.
Three C9 analogs (4, 5, and 6 [SC13]) exhibited lower G-protein efficacy than DAMGO or morphine in heterologous assays, with efficacy comparable to buprenorphine under limited receptor reserve.
Lead compound 6 (SC13) produced mu-opioid-receptor-dependent analgesia with potency similar to morphine.
Unlike morphine, compound 6 (SC13) caused no detectable respiratory depression, hyperlocomotion, constipation, or place conditioning in mice.

Cite This Study

Chakraborty et al. (2021) studied this question.

synapsesocial.com/papers/6ab2071b6ae800ef9e2422cf https://doi.org/10.1021/acs.jmedchem.1c01273

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Implication

Preclinical study demonstrates morphine-like analgesia without respiratory depression or addiction liability in mice, suggesting minimal mu opioid receptor activation can achieve safe pain relief.

A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

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Key Points

Cite This Study

A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

Discussion

Member takes

Implication

Key Points

Cite This Study

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