TY - JOUR

T1 - 3-hydroxypyridazine 1-oxides as carboxylate bioisosteres

T2 - a new series of subtype-selective AMPA receptor agonists

AU - Greenwood, Jeremy R

AU - Mewett, Ken N

AU - Allan, Robin D

AU - Martín, Belén Ortiz

AU - Pickering, Darryl

N1 - Keywords: Alanine; Animals; Carboxylic Acids; Cerebral Cortex; Cloning, Molecular; Cyclic N-Oxides; Dose-Response Relationship, Drug; Electrophysiology; Models, Molecular; Molecular Mimicry; Oocytes; Pyridazines; Pyrimidinones; RNA, Complementary; Radioligand Assay; Rats; Receptors, AMPA; Receptors, Glutamate; Recombinant Proteins; Structure-Activity Relationship; Uracil; Xenopus laevis

PY - 2006/7

Y1 - 2006/7

N2 - 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.

AB - 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.

U2 - 10.1016/j.neuropharm.2006.02.013

DO - 10.1016/j.neuropharm.2006.02.013

M3 - Journal article

C2 - 16631211

VL - 51

SP - 52

EP - 59

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 1

ER -