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Abstract
Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.
Highlights
Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders
MG is a complex natural product of a corynanthidine alkaloid type decorated with a number of functional groups, including enol ether, ester, tertiary amine, indole nitrogen, and aromatic methyl ether, arranged in a specific constitutional and geometrical configuration that underlies its opioid activity
After exploration and optimization of reaction conditions (Supplementary Table 1), we found that borylation is compatible with the MG chemotype
Summary
Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. In search of molecules with robust clinical effects in the area of central nervous system (CNS) disorders and ability to repair synaptic function in the brain, we have been led to atypical modulators of endogenous opioid signaling[1,2,3,4]. In this context, we became interested in the psychoactive plant Mitragyna speciosa that has been used for centuries in Southeast Asia for treatment of pain, fatigue, opium dependence, and a number of other ailments. MG can be extracted from kratom leaf matter in multigram quantities (~1% of dry kratom mass14,15), and there is a strong incentive to develop synthetic methods for direct functionalization of MG, for example, via late-stage C–H functionalization, rather than laborious total synthesis
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