In-vitro characterization of YM872, a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist

The in-vitro pharmacological properties of (2,3-dioxo-7-(1H-imidazol-1-yl)- 6-nitro1,2,3,4-tetrahydro-1-quinoxalinyl)-acetic acid monohydrate, YM872, a novel and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-p ropionate (AMPA)-receptor antagonist were investigated. YM872 is highly water soluble (83 mg mL(-1) in Britton-Robinson buffer) com pared with 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (NBQX), 6-(1H-imidazol- 1-yl)7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) or 6-cyano-7 -nitroquinoxaline-2,3-dione (CNQX). YM872 potently inhibits [H-3]AMPA bindi ng with a Ki (apparent equilibrium dissociation constant) value of 0.096 +/ - 0.0024 mu M. However, YM872 had very low affinity for other ionotropic gl utamate receptors, as measured by competition with [H-3]kainate thigh-affin ity kainate binding site, concentration resulting in half the maximum inhib ition (IC50) = 4.6 +/- 0.14 mu M), [H-3]glutamate (IV-methyl-D-aspartate (N MDA) receptor glutamate binding site, IC50 > 100 mu M) and [H-3]glycine (NM DA receptor glycine-binding site, IC50 > 100 mu M). YM872 competitively ant agonized kainate-induced currents in Xenopus laevis oocytes which express r at AMPA receptors, with a pA(2) value of 6.97 +/- 0.01. In rat hippocampal primary cultures, YM872 blocked a 20-mu M AMPA-induced increase of intracel lular Ca2+ concentration with an IC50 value of 0.82+/-0.031 mu M, and block ed 300-mu M kainate-induced neurotoxicity with an IC50 value of 1.02 mu M. These results show that YM872 is a potent and highly water-soluble AMPA ant agonist with great potential for treatment of neurodegenerative disorders s uch as stroke.