Potency, dissociation kinetics and reversibility of fentanyls and nitazenes by naloxone at the μ opioid receptor

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 5, 2024

Abstract Background and Purpose Fentanyls nitazenes are μ opioid receptor agonists responsible for a large number of overdose deaths. Here, we compared the potency, dissociation kinetics antagonism by naloxone at several fentanyl nitazene analogues them to morphine DAMGO. Experimental Approach In vitro assays G protein activation signalling arrestin recruitment were performed. AtT20 cells expressing receptors loaded with membrane potential dye changes in fluorescence used determine agonist susceptibility naloxone. BRET experiments undertaken HEK293T receptors, assess Gi β-arrestin 2 recruitment. Key Results The rate from varied, morphine, DAMGO, alfentanil dissociating rapidly whereas isotonitazene, etonitazene, ohmefentanyl carfentanil dissociated slowly. Slowly more resistant For carfentanil, slow was not due kinase-mediated as its affected inhibition GRKs Compound 101. relative potencies fentanyls much lower than that previously observed vivo experiments. Conclusions Implications With nitazenes, slowly dissociate receptor, is pseudo competitive. overdoses involving higher doses may be required reversal those normally reverse heroin overdose. What already known “Fentanyls” “nitazenes” potent receptor. does this study add Some less sensitive clinical significance More

Язык: Английский

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Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous ¹H NMR-Based logP/D Determination, Both Separately and in Mixtures

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Июль 16, 2024

A systematic study of trends in the lipophilicity prominent representatives opioid family, including natural, semisynthetic, synthetic, and endogenous neuropeptide opioids, is described. This was enabled by a straightforward 1H NMR-based logP/D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, new enables direct simultaneous logD mixtures, overcoming high sensitivity this family to measurement conditions, which critical when exact ΔlogD values matched pairs required. Interpretation experimental ΔlogD7.4 selected pairs, focusing inter alia on 3-OMe 14-OMe motifs morphinan suggested with aid DFT calculations may be useful discovery therapeutics.

Язык: Английский

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In vitro and in vivo study of butyrylfentanyl and 4‐fluorobutyrylfentanyl in female and male mice: Role of the CRF₁ receptor in cardiorespiratory impairment

British Journal of Pharmacology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 4, 2024

Abstract Background and Purpose Fentanyl analogues have been implicated in many cases of intoxication death with overdose worldwide. The aim this study is to investigate the pharmaco‐toxicology two fentanyl analogues: butyrylfentanyl (BUF) 4‐fluorobutyrylfentanyl (4F‐BUF). Experimental Approach In vitro, we measured agonist opioid receptor efficacy, potency, selectivity ability promote interaction μ G protein β‐arrestin 2. vivo, evaluated thermal antinociception, stimulated motor activity cardiorespiratory changes female male CD‐1 mice injected BUF or 4F‐BUF (0.1–6 mg·kg −1 ). Opioid specificity was investigated using naloxone (6 We possible role stress increasing toxicity corticotropin‐releasing factor 1 (CRF ) antagonist antalarmin (10 Key Results Agonists displayed following rank potency at receptors: > BUF. behaved as partial agonists for 2 pathway, whereas did not recruitment. revealed sex differences impairments but antinociception induced by 4F‐BUF. Antalarmin alone effective blocking respiratory impairment both sexes combination significantly enhanced reversal mice. Conclusion Implications study, uncovered a novel mechanism which synthetic opioids induce depression, shedding new light on CRF receptors agonists.

Язык: Английский

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Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the μ‐opioid receptor

British Journal of Pharmacology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 22, 2024

Abstract Background and Purpose Fentanyls nitazenes are μ‐opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we determined the potency, dissociation kinetics antagonism by naloxone at μ several fentanyl nitazene analogues, compared to morphine DAMGO. Experimental Approach In vitro assays G protein activation signalling arrestin recruitment were performed. AtT20 cells expressing receptors loaded with membrane potential dye changes in fluorescence used determine agonist susceptibility naloxone. BRET experiments undertaken HEK293T assess Gi β‐arrestin 2 recruitment. Key Results The apparent rate from varied: morphine, DAMGO, alfentanil dissociated rapidly, whereas isotonitazene, etonitazene, ohmefentanyl carfentanil slowly. Slowly dissociating more resistant For carfentanil, slow was not because kinase‐mediated as its increased inhibition protein‐coupled kinases (GRKs) Compound 101. relative potencies fentanyls much lower than that previously observed vivo experiments. Conclusions Implications With slowly dissociate receptor, is pseudo‐competitive. overdoses involving nitazenes, higher doses may be required reversal those normally reverse heroin overdose.

Язык: Английский

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Lateral periaqueductal gray participate in the regulation of irritable bowel syndrome induced by chronic restraint stress

Neurobiology of Disease, Год журнала: 2024, Номер unknown, С. 106758 - 106758

Опубликована: Дек. 1, 2024

Irritable bowel syndrome (IBS) is a functional disorder defined by recurrent abdominal pain, coupled with irregular habits and alterations in the frequency as well consistency of stool. At present, IBS considered disease gut-brain interaction, an increasing number studies are focusing on brain-gut axis. However, brain regions associated have not been fully studied yet. In this study, we utilized chronic restraint stress (CRS) model to evoke IBS-like symptoms mice, which were accompanied anxiety-like behaviors hyperalgesia. Through cFOS staining, observed activation lateral periaqueductal gray (LPAG) mice after CRS. By inhibiting activity LPAG through tetanus toxin or chemogenetics, found that could be relieved, whereas chemogenetic induced symptoms. Finally, classic analgesic drug sufentanil it alleviate CRS-induced

Язык: Английский

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