Journal
ACS CENTRAL SCIENCE
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.2c00442
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Funding
- National Institute of Mental Healths Psychoactive Drug Screening Program [HHSN-271-2018-00023-C]
- National Institutes of Health [R35 GM122606, TL1TR002551, DA031927, DA048490]
- Skaggs Graduate School
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This study presents a method for the synthesis of collybolide and demonstrates that it is not a KOR agonist. This finding has significant implications for ongoing research on the pharmaceutical, medical, and societal potential of collybolide.
The fungal metabolite collybolide has attracted attention as a non-nitrogenous, potent, and biased agonist of the kappa-opioid receptor (KOR). Here, we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective alpha- benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, indicating that collybolide has been mischaracterized as a KOR agonist. Given the pharmaceutical, medical, and societal interest in collybolide as a next-generation antipruritic and analgesic, this refutation of KOR activity has important ramifications for ongoing studies. Classification of collybolide as a new non-nitrogenous, KOR-selective, potent agonist with the same clinical potential as salvinorin A seems to have been premature.
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