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Pharmacologic Characterization of Substituted Nitazenes at µ, κ, and Δ Opioid Receptors Suggests High Potential for Toxicity.
Kozell, Laura B; Eshleman, Amy J; Wolfrum, Katherine M; Swanson, Tracy L; Bloom, Shelley H; Benware, Sheila; Schmachtenberg, Jennifer L; Schutzer, Kamryn A; Schutzer, William E; Janowsky, Aaron; Abbas, Atheir I.
Afiliación
  • Kozell LB; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Eshleman AJ; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Wolfrum KM; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Swanson TL; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Bloom SH; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Benware S; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Schmachtenberg JL; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Schutzer KA; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Schutzer WE; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Janowsky A; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon.
  • Abbas AI; VA Portland Health Care System (L.B.K., A.J.E., K.M.W., T.L.S., S.H.B., S.B., J.L.S., K.A.S., W.E.S., A.J., A.I.A.), Departments of Psychiatry (L.B.K., A.J.E., T.L.S., W.E.S., A.J., A.I.A.), and Behavioral Neuroscience (L.B.K., A.J., A.I.A.), Oregon Health and Science University, Portland, Oregon ab
J Pharmacol Exp Ther ; 389(2): 219-228, 2024 04 18.
Article en En | MEDLINE | ID: mdl-38453524
ABSTRACT
The benzimidazole opioids (substituted nitazenes) are highly potent µ opiod receptor (MOR) agonists with heroin- or fentanyl-like effects. These compounds have caused hospitalizations and fatal overdoses. We characterized the in vitro pharmacology and structure-activity relationships of 19 nitazenes with substitutions at three positions of the benzimidazole core. Affinities were assessed using agonist radioligand binding assays at human µ, κ, and Δ opioid receptors (MOR, KOR, and DOR, respectively) heterologously expressed in CHO cells. Notably, for MOR binding, nine substituted nitazenes had significantly higher affinities than fentanyl including N-pyrrolidino etonitazene, N-pyrrilidino isonitazene, and N-desethyl isotonitazene; 13 had subnanomolar affinities. Only metodesnitazene and flunitazene had significantly lower affinities than fentanyl. Affinities for the substituted nitazenes at KOR and DOR relative to MOR were 46- to 2580-fold and 180- to 1280-fold lower, respectively. Functional activities were assessed using [35S]GTPγS binding assays. Four nitazenes had subnanomolar potencies at MOR N-pyrrolidino etonitazene, N-pyrrilidino isonitazene, N-pyrrilidino protonitazene and N-desethyl isotonitazene. Ten substituted nitazenes had significantly higher potencies than fentanyl. All tested nitazenes were full MOR agonists. Potencies at KOR and DOR relative to MOR were 7.3- to 7920-fold and 24- to 9400-fold lower, respectively. Thus, many of these compounds are high affinity/high potency MOR agonists with elevated potential to elicit toxicity and overdose at low doses. SIGNIFICANCE STATEMENT Substituted nitazenes are a growing public health threat. Although the 19 nitazenes tested vary in their opioid receptor pharmacology, a number are very high affinity, high potency, and high efficacy compounds- higher than fentanyl. Their pharmacology suggests high potential for harm.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Opioides delta / Receptores Opioides kappa Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Opioides delta / Receptores Opioides kappa Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos