title: Reduced efficacy of the intravenous anesthetic agent AZD3043 at GABA(A) receptors with β2 (N289M) and β3 (N290M) point-mutations.
abstract: AZD3043 (previously named THRX-918661) is a novel short-acting intravenous anesthetic agent in clinical trials. Although AZD3043 is a positive modulator at the γ-aminobutyric acid (GABA)(A)-receptor, its potency and efficacy have not been characterized in detail. Nor is it known whether the point-mutations in the β-subunit of the GABA(A)-receptor that dramatically reduce the anesthetic effect of propofol (i.e. β2 (N289M) and β3 (N290M)), also influence the effect of AZD3043. This study investigated the in vitro pharmacology of AZD3043 at the most common human GABA(A) receptor subtypes. Subunits of four human wild-type (α1β2, α1β2γ2, α2β2γ2 and α2β3γ2) and two mutant (α1β2(N289M)γ2 and α2β3(N290M)γ2) GABA(A) receptor channels were introduced into Xenopus oocytes and studied with two-electrode voltage-clamp. AZD3043 potentiated and directly activated the α1β2γ2, α2β2γ2 and α2β3γ2 GABA(A) receptor subtypes. Moreover, both potency and efficacy of AZD3043 were reduced at the mutant α1β2(N289M)γ2 and α2β3(N290M)γ2 subtypes. AZD3043 increased the GABA response also in GABA(A) receptors lacking the γ2-subunit, i.e. α1β2. In conclusion, AZD3043 is a positive modulator and a direct agonist at human GABA(A) receptors and is not dependent on the γ2-subunit for its effect. Similar to propofol, the effect of AZD3043 is dramatically reduced by point-mutations in the β2(N289M) and β3(N290M) subunits, indicating similar molecular mechanisms of action for propofol and AZD3043 at the human GABA(A) receptor.
authors.affiliation: Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital, SE-17176 Stockholm, Sweden. malin.jonsson.fagerlund@ki.se
authors.forename: Malin
authors.initials: M
authors.lastname: Jonsson Fagerlund
authors.forename: Johanna
authors.initials: J
authors.lastname: Sjödin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dabrowski
authors.forename: Johannes
authors.initials: J
authors.lastname: Krupp
mesh_terms: D061605:Administration, Intravenous; D000777:Anesthetics / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D010648:Phenylacetates / Q000008:administration & dosage* / Q000494:pharmacology*; D017354:Point Mutation; D021122:Protein Subunits / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
chemical_list: C573579:AZD-3043; D000777:Anesthetics; D058785:GABA-A Receptor Agonists; D010648:Phenylacetates; D021122:Protein Subunits; D011963:Receptors, GABA-A