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Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABAA receptor and CaV2.2 channel.
Tae, Han-Shen; Ortells, Marcelo O; Yousuf, Arsalan; Xu, Sophia Q; Akk, Gustav; Adams, David J; Arias, Hugo R.
Afiliación
  • Tae HS; Molecular Horizons/Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia. Electronic address: hstae@uow.edu.au.
  • Ortells MO; Facultad de Medicina, Universidad de Morón, and CONICET, Morón, Argentina.
  • Yousuf A; Molecular Horizons/Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
  • Xu SQ; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
  • Akk G; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
  • Adams DJ; Molecular Horizons/Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
  • Arias HR; Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, USA.
Biochem Pharmacol ; 223: 116183, 2024 05.
Article en En | MEDLINE | ID: mdl-38580167
ABSTRACT
In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ibogainalog (IBG) at heterologously-expressed rat (r) and human (h) nicotinic acetylcholine receptors (nAChRs), the rα1ß2γ2L γ-aminobutyric acid type A receptor (GABAAR), and the human voltage-gated N-type calcium channel (CaV2.2 channel). Both compounds inhibited the nAChRs with the following receptor selectivity α9α10 > α7 > α3ß2 â‰… α3ß4, indicating that ß2/ß4 subunits are relatively less important for their activity. The potencies of TBG and IBG were comparable at hα7 and hα9α10 subtypes, and comparable to their rat counterparts. TBG- and IBG-induced inhibition of rα7 was ACh concentration-independent and voltage-dependent, whereas rα9α10 inhibition was ACh concentration-dependent and voltage-independent, suggesting that they interact with the α7 ion channel pore and α9α10 orthosteric ligand binding site, respectively. These results were supported by molecular docking studies showing that at the α7 model TBG forms stable interactions with luminal rings at 9', 13', and 16', whereas IBG mostly interacts with the extracellular-transmembrane junction. In the α9α10 model, however, these compounds interacted with several residues from the principal (+) and complementary (-) sides in the transmitter binding site. Ibogaminalog (DM506) also interacted with a non-luminal site at α7, and one α9α10 orthosteric site. TBG and IBG inhibited the GABAAR and CaV2.2 channels with 10 to 30-fold lower potencies. In sum, we show that TBG and IBG inhibit the α7 and α9α10 nAChRs by noncompetitive and competitive mechanisms, respectively, and with higher potency than the GABAAR and CaV2.2 channel.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Nicotínicos Límite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Nicotínicos Límite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido