Binding preference at the μ-opioid receptor underlies distinct pharmacology of cyclopropyl versus valeryl analogs of fentanyl Journal Article
| Authors: | Xie, B.; Le Rouzic, V. P.; Goldberg, A.; Tsai, M. H. M.; Chen, L.; Zhang, T.; Sinha, A.; Pan, Y. X.; Baumann, M. H.; Shi, L. |
| Article Title: | Binding preference at the μ-opioid receptor underlies distinct pharmacology of cyclopropyl versus valeryl analogs of fentanyl |
| Abstract: | Illicitly manufactured fentanyl is driving the current opioid crisis, and various fentanyl analogs are appearing in recreational drug markets worldwide. To assess the potential health risks posed by fentanyl analogs, it is necessary to understand structure-activity relationships for these compounds. Here we compared the pharmacology of two structurally related fentanyl analogs implicated in opioid overdose: cyclopropylfentanyl and valerylfentanyl. Cyclopropylfentanyl has a three-carbon ring attached to the carbonyl group on the fentanyl scaffold, whereas valerylfentanyl has a four-carbon chain at the same position. In vitro assays examining μ-opioid receptor (MOR) coupling to G proteins in CHO cells showed that cyclopropylfentanyl is a full agonist (EC50 = 8.6 nM, %Emax = 113%), with potency and efficacy similar to fentanyl (EC50 = 10.3 nM, %Emax = 113%). By contrast, valerylfentanyl is a partial agonist at MOR (EC50 = 179.8 nM, %Emax = 60%). Similar results were found in assays assessing MOR-mediated β-arrestin recruitment in HEK cells. In vivo studies in male CD-1 mice demonstrated that both fentanyl analogs induce naloxone-reversible antinociception and respiratory suppression, but cyclopropylfentanyl is 100-times more potent as an antinociceptive agent (ED50 = 0.04 mg/kg, s. c.) than valerylfentanyl (ED50 = 4.0 mg/kg, s. c.). Molecular simulation results revealed that the alkyl chain of valerylfentanyl cannot be well accommodated by the active state of MOR and may transition the receptor toward an inactive state, converting the fentanyl scaffold to a partial agonist. Taken together, our results suggest that cyclopropylfentanyl presents much greater risk of adverse effects when compared to valerylfentanyl. Moreover, the summed findings may provide clues to the design of therapeutic opioids with reduced adverse side effects. © 2023 |
| Keywords: | controlled study; unclassified drug; human cell; drug efficacy; nonhuman; binding affinity; animal cell; mouse; molecular dynamics; animal experiment; in vivo study; drug potency; drug structure; in vitro study; drug design; structure activity relation; structure-activity relationship; drug receptor binding; morphine; guanine nucleotide binding protein; mu opiate receptor; fentanyl; analgesic activity; drug overdose; health hazard; antinociception; human; male; article; molecular dynamics simulations; μ-opioid receptor; ec50; cd-1 mouse; fentanyl derivative; beta arrestin; cyclopropylfentanyl; valerylfentanyl; cho cell line |
| Journal Title: | Neuropharmacology |
| Volume: | 227 |
| ISSN: | 0028-3908 |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2023-04-01 |
| Start Page: | 109442 |
| Language: | English |
| DOI: | 10.1016/j.neuropharm.2023.109442 |
| PUBMED: | 36731721 |
| PROVIDER: | scopus |
| PMCID: | PMC9974845 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. -- Export Date: 1 March 2023 -- Source: Scopus |
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