Site Selective C-H Functionalization of Mitragyna Alkaloids Reveals a Molecular Switch for Tuning Opioid Receptor Signaling Efficacy

Bhowmik, Srijita; Galeta, Juraj; Havel, Václav; Nelson, Melissa; Faouzi, Abdelfattah; Bechand, Benjamin; Fiala, Tomas; Hunkele, Amanda; Kruegel, Andrew; Majumdar, Susruta; Javitch, Jonathan A.; Sameš, Dalibor

doi:10.26434/chemrxiv.12799787

Cited by 8 publications

(18 citation statements)

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“…The anti‐nociceptive effects of both mitragynine and 7‐OH mitragynine were abolished in μ receptor knockout mice, but not in mice lacking either the δ or the κ opioid receptors (Kruegel et al, 2019). The analgesic effects of kratom, together with the low rates of acute toxicity or overdose following its ingestion (Veltri & Grundmann, 2019), have attracted considerable attention in the search for novel, safer opioid‐based analgesics amid the current opioid crisis (Bhowmik et al, 2021; Chakraborty, Diberto, Faouzi, et al, 2021; Chakraborty, Uprety, Daibani, et al, 2021; Gutridge et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Hill

Kruegel

Javitch

et al. 2022

British J Pharmacology

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Background and Purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious μ receptor agonist. While both mitragynine and 7-OH mitragynine can induce anti-nociception in mice, recent evidence suggests that 7-OH mitragynine formed as a metabolite is sufficient to explain the anti-nociceptive effects of mitragynine. However, the ability of 7-OH mitragynine to induce μ receptor-dependent respiratory depression has not yet been studied.Experimental Approach: Respiration was measured in awake, freely moving, male CD-1 mice, using whole body plethysmography. Anti-nociception was measured using the hot plate assay. Morphine, mitragynine, 7-OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally.

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Section: Introductionmentioning

confidence: 99%

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Hill

Kruegel

Javitch

et al. 2022

British J Pharmacology

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“…48 In more recent that have revealed further insight into the molecular mechanisms of analgesia and opioid-induced side effects. [12][13][14]49 The results from this SAR study add to this tradition by providing new chemical scaffolds that can engage the µOR binding pocket in unique ways. To rationalize the SAR trends we observed, we used induced-fit docking (Maestro) to identify potential binding modes and interactions made between two of the more potent derivatives (19 and 33) and the µOR (Figure 5).…”

Section: Discussionmentioning

confidence: 80%

“…15 Nitrile analog 10 was synthesized from 9 in a palladium-catalyzed cyanation with Zn(CN)2 as the nitrile source. 23 Suzuki-Miyaura cross-couplings were used to append aromatic and heterocyclic rings (11)(12)(13)(14)(15)(16). 15 In addition to introducing substitutions at C10, reduction of 9 with formic acid as the hydride source provides 2.…”

Section: Aromatic Modifications (C10 and C11)mentioning

confidence: 99%

“…12 More recently, of the structure-activity relationships (SAR) studies on the mitragynine alkaloids have revealed how even small changes to the scaffold allow for the fine-tuning of opioid receptor signaling. 8,[13][14][15] In addition to providing new chemical tools to probe the opioid receptor and its function, the development of these novel classes of opioids offers new opportunities to develop potential analgesics.…”

Section: Introductionmentioning

confidence: 99%

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Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor

Hennessy

Gutridge

French

et al. 2022

Preprint

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Akuammine (1) and pseudo-akuammigine (2) are indole alkaloids found in the seeds of the akuamma tree (Picralima nitida) that are used as a traditional treatment for pain in West Africa. Both alkaloids are agonists of the mu-opioid receptor (µOR); however, they produce minimal effects in animal models of antinociception, likely due to their modest potency. To further probe the interactions of 1 and 2 at the opioid receptors, we have prepared a collection of semi-synthetic derivatives with modifications to the C10, C11, C16, and N1 positions of the indole core. Evaluation of this collection at the µOR and kappa opioid receptor (κOR) revealed structural-activity relationship trends and derivatives with improved potency at the µOR. Most notably, the introduction of a phenethyl moiety to the N1 of 2 produces a 70-fold increase in potency and a 7-fold increase in selectivity for the µOR. The in vitro potency of this compound was reflected in vivo in rodents, producing an ED50 = 77.6 mg/kg and 77.1 mg/kg in a tail-flick antinociception assay and a hot-plate assay, respectively. The improved potency of these analogs highlights the promise of exploring natural product scaffolds that can be used to probe the opioid receptors.

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“…DAMGO and fentanyl were excluded from this analysis because of their different chemical composition and expected unique mode of binding with respect to the other molecules in the data set. The MD simulations of SC1, SC3, SC4, SC11, SC12, SC13, 11F, 37,38 morphine, and buprenorphine (See Appendix 1-Table 5 for efficacy data), were carried out using the same simulation parameters and protocol used in our previous work on 7OH and mitragynine. 39 A statistical analysis of structural interaction fingerprints (SIFts) derived from these simulations and whose average probabilities are listed in Appendix 1-Table 6 for each ligand, yielded 8 statistical models that best recapitulate the negative logarithm of experimental G protein Emax values obtained for each ligand (see Appendix 1-Figure 4, Gi-1 Emax was used for ligands).…”

Section: Sc11-13 Form Different Interactions With Mor Compared To Morphine and Buprenorphinementioning

confidence: 99%

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

Chakraborty

DiBerto

Faouzi

et al. 2021

Preprint

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Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratom and its natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal beta-arrestin2 recruitment. To further investigate the structure activity relationships of G-protein potency, efficacy, and beta-arrestin2 recruitment, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl (SC11), methyl (SC12), 3-furanyl (SC13), were further characterized using a panel of in vitro and ex vivo electrophysiology assays. All three compounds were partial agonists with lower efficacy than both DAMGO and morphine in heterologous G-protein assays and synaptic physiology. SC11-13 also showed lower recruitment of both β-arrestin subtypes compared to DAMGO, and in assays with limited MOR receptor reserve, the G-protein efficacy of SC11, SC12 and SC13 was comparable to buprenorphine. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together, these results suggest that MOR agonists with a G-protein efficacy profile similar to buprenorphine can be developed into opioids that are effective analgesics with greatly reduced liabilities.

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Site Selective C-H Functionalization of Mitragyna Alkaloids Reveals a Molecular Switch for Tuning Opioid Receptor Signaling Efficacy

Cited by 8 publications

References 0 publications

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

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