3-hydroxypyridazine 1-oxides as carboxylate bioisosteres: a new series of subtype-selective AMPA receptor agonists.
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 to the binding mode observed in the crystal structure of willardiine bound to GluR2-S1S2. The results indicate that the 3-hydroxypyridazine 1-oxide moiety can function as an outstanding carboxylate mimic at AMPA-Rs, leading the way to further fine-tuning of subtype selectivity. This little-explored molecular motif may find wider application in medicinal chemistry.
Greenwood
Jeremy R
JR
Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK 2100 Copenhagen, Denmark.
Mewett
Ken N
KN
Allan
Robin D
RD
Martín
Belén Ortiz
BO
Pickering
Darryl S
DS
D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D066298:In Vitro Techniques; D008958:Models, Molecular; D018716:Molecular Mimicry; D009865:Oocytes / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists*; D017470:Receptors, Glutamate / Q000378:metabolism; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis
D002264:Carboxylic Acids; D003497:Cyclic N-Oxides; D011724:Pyridazines; D011744:Pyrimidinones; D018075:RNA, Complementary; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D011994:Recombinant Proteins; C002872:willardiine; D014498:Uracil; D000409:Alanine