Quinazolone-Alkyl-Carboxylic Acid Derivatives Inhibit Transmembrane Ca²⁺Ion Flux to (+)-(S)-α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid

Abstract

Comparison of the kinetics of the inward Ca 2ϩ ion flux to (S)-␣-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid [(S)-AMPA] in cerebrocortical homogenates and that of the previously reported transmembrane Na ϩ ion influx mediated by an AMPA receptor in hippocampal homogenates established that the agonist-induced opening of the AMPA receptor channels occurs in two kinetically distinguishable phases. Here we report that the 2-methyl-4-oxo-3H-quinazoline-3-acetic acid (Q1) inhibits the major slow-phase response specifically, whereas the acetyl piperidine derivative (Q5) is a more potent inhibitor of the fast-phase response. Both the quinazolone-3-propionic acid (Q2) and the quinazolone-3-acetic acid methyl ester (Q3) enhanced the slow-phase response to (S)-AMPA.The information provided by docking different Q1, Q2, and Q5 models at the ligand-binding core of iGluRs were used to define agonistic and antagonistic modes of interactions. Based on the effects of quinazolone-3-alkyl-carboxylic acid derivatives on specific [3 H]Glu binding and kinetically distinguishable Ca 2ϩ ion permeability responses to (S)-AMPA and molecular modeling, the fast-and the slow-phase (S)-AMPA-elicited Ca 2ϩ ion fluxes were corresponded to different subunit compositions and degrees of S1S2 bridging interaction relative to substitution of kainate thereupon. Substitutions of agonists and antagonists into the iGluR2 S1S2 ligand binding core induced different modes of domain-domain bridging.The seminal information on the structure of an ionotropic glutamate receptor (iGluR) in complex with the neurotoxic agonist, kainate (Armstrong et al., 1998), together with the concept of the autonomous ligand-binding core for all iGluRs (Paas, 1998), opened up the development of drugs targeting iGluR more specifically. Polar groups dock kainate at the interdomain pocket formed by two polypeptide segments, S1 and S2, via multiple interactions with the amino acid residues of the ligand-binding core. Here we describe effects of quinazolone-alkyl-carboxylic acid derivatives (QXs; Fig. 1) on the rates of transmembrane Ca 2ϩ ion influx to (S)-AMPA. In addition, measurements on specific [3 H]Glu binding in rat brain cortical homogenates containing resealed plasmalemmal vesicles and nerve endings were performed to clarify the subunit compositions of receptors in the interpretation of the data as well as to justify the use of the iGluR2-S1-S2 crystal structure to model the ligand docking that modulates Ca 2ϩ ion flux. We attempt, on the basis of these results, 1) to integrate kinetics, pharmacological profile, and three-dimensional structure of the receptor-ligand complex to understand the molecular features of the Glu-gated ion channel-ligand interactions, and 2) to identify prerequisites for AMPA receptor agonist and antagonist specifics, by relating results from measurements of an AMPA receptor function with the relative position of the agonist-binding-site domains.

Liquid chromatographic enantiomer separations of novel quinazolone derivatives on quinine carbamate based chiral stationary phases using hydro-organic mobile phases

“…The target compounds of this contribution, the quinazolones are considered to be important heterocyclic substances with diverse biological and pharmacological activities depending on the position and properties of the ring substituents [16][17][18][19][20]. Recently, a set of novel imidazo[1,5-b]-quinazoline-1,5-diones (see Fig.…”

Novel Secoergoline Derivatives Inhibit Both GABA and Glutamate Uptake in Rat Brain Homogenates: Synthesis, in Vitro Pharmacology, and Modeling

“…34 Geometry of each ligand molecule was obtained upon molecular mechanics energy minimization of the positively charged form using simplexing and applying Powell and BFGS algorithm alternately. Docking procedures were performed as follows: 6 ligand molecules were positioned in the hypothesized manner (CdO group of COOH faced to Tyr-140 of TM3 and Thr-89 of TM2, OH group of COOH faced to Asn-137 and N faced to Ser-133). After minor manual adjustments for finding a favorable initial position for the ligand, the energy of the system was minimized throughout the docking procedure during which neither site nor ligand geometry was fixed.…”

“…Development of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists may have a role for the control of symptoms. Indeed, suppression of seizures in a low-[Mg 2+ ] ion model of experimental epilepsy was observed with the use of a quinazolone-alkyl-carboxylic acid derivative, known to block ( S )(+)AMPA-induced transmembrane Ca 2+ ion influx …”

“…Indeed, suppression of seizures in a low-[Mg 2+ ] ion model of experimental epilepsy was observed with the use of a quinazolone-alkyl-carboxylic acid derivative, 5 known to block (S)(+)AMPA-induced transmembrane Ca 2+ ion influx. 6 Among the rational strategies, the most widely used way to develop new antiepileptic drugs is based on the GABA hypothesis of epilepsy. 7 Accordingly, impairment of GABAergic pathways is of deciding importance for the pathogenesis of several types of epilepsy.…”

Synthesis of Novel Quinazoline Derivatives via Pyrimidine ortho-Quinodimethane

“…The presence of a pyrimidine nucleus in many heterocyclic compounds, for example, the quinazolines, often leads to very interesting biological and pharmaceutical activities [ 1 , 2 ] so many methods for preparing quinazolines are reported in the literature [ 3 , 4 ]. In this work, we have developed an original method to prepare novel quinazoline derivatives based on cycloaddition between 2,4- disubstituted pyrimidine ortho -quinodimethanes and suitable dienophiles [ 5 ].…”