Activation of the μ‐opioid receptor by alicyclic fentanyls: Changes from high potency full agonists to low potency partial agonists with increasing alicyclic substructure

Abstract

Fentanyl analogs represent an important group of new psychoactive substances and knowing their efficacy and potency might assist in interpreting observed concentrations. The potency of fentanyl analogs can be estimated from in vitro studies and can be used to establish structure-activity relationships. In this study, recombinant CHO-K1 cells (AequoScreen) expressing the human μ-opioid receptor were used to establish dose-response curves via luminescent analysis for cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, and 2,2,3,3-tetramethylcyclopropylfentanyl (TMCPF), on three separate occasions, using eight different concentrations in an eight-fold serial dilution in triplicates starting at 60 μM. Fentanyl was used as a full agonist reference while morphine and buprenorphine were included for comparison. Cyclopropylfentanyl (EC 50 = 4.3 nM), cyclobutylfentanyl (EC50 = 6.2 nM), and

Selective C–H activation of unprotected allylamines by control of catalyst speciation

“…For reference, the potency of 5i is comparable to morphine with an EC50 of 430 nm. 65 In conclusion, we have demonstrated how simple mono-protected amino acid ligands can be used to protect allylamines from rapid decomposition, which in turn protects the Pd catalyst, thereby allowing a reaction that had previously given trans-addition products through a directed Mizoroki-Heck reaction to become selective for cis-addition through a directed C-H activation pathway. This technology allows for a variety of 2° and 3° allylamine substrates to be derivatised, including carbocyclic alkenes, which were not previously accessible with other processes.…”

“…Interestingly, this was even lower than the previously reported EC50 for fentanyl determined from mini-Gi and β-arrestin recruitment assays, indicating the suitability of the γ9 assay. 65 For 5i, the γ9 assay provided an EC50 of 505 ± 129 nM (Figure 2c). For reference, the potency of 5i is comparable to morphine with an EC50 of 430 nm.…”

Pharmacokinetics and pharmacodynamics of cyclopropylfentanyl in male rats

“…There is scant information available regarding the in vivo pharmacodynamics of cyclopropylfentanyl (EMCDDA 2018a ). In vitro studies show that cyclopropylfentanyl displays a binding affinity in the low nanomolar, or sub-nanomolar, range for µ-opioid receptors (Baumann et al 2018 ; Eshleman et al 2020 ; Hassanien et al 2020 ; Wilde et al 2019 ; Åstrand et al 2020a ; Åstrand et al 2020b ). A preclinical study from the 1960s compared the antinociceptive effects of various fentanyl analogs and reported that cyclopropylfentanyl exhibits a potency somewhat lower than fentanyl but higher than acetylfentanyl and butyrfentanyl (Janssen and Van der Eycken 1968 ).…”

“…However, information about the in vivo biological effects of cyclopropylfentanyl is lacking. In vitro studies show that the drug is a fully efficacious µ-opioid receptor agonist with a receptor binding affinity in the low nanomolar range and potency similar to fentanyl (Eshleman et al 2020;Hassanien et al 2020;Wilde et al 2019;Åstrand et al 2020a;Åstrand et al 2020b). An animal study performed in the 1960s compared the antinociceptive effects of different fentanyl analogs in mice and rats and reported that cyclopropylfentanyl was slightly less potent than fentanyl but more potent than acetylfentanyl, butyrfentanyl, as well as the reference substance pethidine (Janssen and Van der Eycken 1968).…”

“…Because of the high potency of cyclopropylfentanyl, the concentrations found in biological samples are low (Roda et al 2019 ; Åstrand et al 2020b ). Blood concentrations of cyclopropylfentanyl reported in fatal overdoses were in the range of 0.80–286 ng/mL (Bergh et al 2018 ; Brede et al 2019 ; Brockbals et al 2018 ; Busardo et al 2019 ; Danaceau et al 2020 ; EMCDDA 2018a ; Fagiola et al 2019 ; Fogarty et al 2018 ; Lee et al 2019 ; Maher et al 2018 ; Matey et al 2020 ), whereas the blood concentrations in non-fatal intoxications were 51 and 76 ng/mL (Müller et al 2019 ).…”