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.

Center for Clinical Pharmacology St Louis College of Pharmacy and Washington University School of Medicine St Louis MO 63110 USA

Department of Chemistry Columbia University New York NY USA

Department of Neurology and Molecular Pharmacology Memorial Sloan Kettering Cancer Center New York NY 10021 USA

Department of Neuroscience and Cell Biology Rutgers University New Jersey NJ 08854 USA

Department of Psychiatry and Department of Molecular Pharmacology and Therapeutics Columbia University New York NY USA

Division of Molecular Therapeutics New York State Psychiatric Institute New York NY USA

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 160 00 Prague 6 Czech Republic

Laboratory of Organic Chemistry ETH Zürich 8093 Zürich Switzerland

NeuroTechnology Center at Columbia University New York NY USA

The Zuckerman Mind Brain Behavior Institute at Columbia University New York NY USA

University of California San Diego La Jolla CA 92161 USA

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