3-hydroxypyridazine 1-oxides as carboxylate bioisosteres: a new series of subtype-selective AMPA receptor agonists

Neuropharmacology
Jeremy R GreenwoodDarryl S Pickering

Abstract

Three positional isomers (compounds 1, 2, and 3) of 1-uracilylalanine (willardiine) based on a 3-hydroxypyridazine 1-oxide scaffold with an alanine side-chain at positions 4 (1), 5 (2) or 6 (3) were tested for binding to recombinant homomeric AMPA receptor (AMPA-R) subtypes GluR1-4, as well for excitatory activity on the rat cortical wedge preparation. 1 had approximately 30 times higher affinity than willardiine while showing a similar selectivity profile, i.e. 22-fold selectivity for GluR1/2 over GluR3/4. The GluR1-4 affinities of 3 were similar to 1, however, its 31-fold selectivity for GluR1/2 over GluR3/4 is the highest yet observed among azine-based glutamate analogues. The non-isosteric congener 2 showed weaker binding to AMPA-Rs. In the cortical wedge, 1 evokes similar responses to AMPA, while 3 and 2 are 10- and 100-fold weaker, respectively. Dose-response curves on Xenopus laevis oocytes expressing GluR1-4(flip) confirmed that 1 and 3 are potent GluR1/2 receptor agonists (EC(50)s from 0.26 to 1.7microM) but are 10- to 160-fold less potent at GluR3/4. The structures, potencies and selectivities of this new class of AMPA agonists are compared with those of willardiine, 5-fluorowillardiine and azawillardiine, referring t...Continue Reading

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Citations

Aug 23, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Michael J Minzenberg, Cameron S Carter
Sep 4, 2013·Acta Crystallographica. Section D, Biological Crystallography·Christian KrintelJette S Kastrup
Aug 19, 2010·Pharmacological Reviews·Stephen F TraynelisRay Dingledine
Dec 15, 2015·Journal of Medicinal Chemistry·Ewa SzymanskaTommy N Johansen
Jan 26, 2010·Bioorganic & Medicinal Chemistry·James J Fleming, Pamela M England
Nov 13, 2008·Proteins·Ahmed H AhmedRobert E Oswald
Apr 26, 2007·Journal of Medicinal Chemistry·Stine B VogensenPovl Krogsgaard-Larsen

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