Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists

Abstract

We describe a new class of subunit-selective antagonists of N-methyl D-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is noncompetitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one), a noncompetitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of noncompetitive subunit-selective NMDA receptor antagonists.

Figure 1

Structures for CP-465,022 (1), (E)-4-(2-(3-nitrostyryl)-4-oxoquinazolin-3(4H)-yl)benzoic acid (2), and (E)-3-(2-methoxyphenyl)-2-(2-nitrostyryl)quinazolin-4(3H)-one (3).

Figure 2

Mean composite concentration-effect curves are shown for NR1/NR2A, NR1/NR2B, NR1/NR2C, NR1/NR2D, GluR1, GluR6 for compounds (A) 46 and (B) 72; error bars are SEM. 2-hydroxypropyl-β-cyclodextrin (1 mM) was included in solutions of 30 and 100 μM 72 and 100 μM for 46. For compound 46, recordings of NMDA and AMPA receptor responses were made from 16-28 oocytes per receptor; oocytes were isolated from 3-5 different frogs. For compound 72, recordings of NMDA and AMPA receptor responses were made from 11-15 oocytes from 3 batches of oocytes from different frogs. No significant effect was observed for 30 μM 46 or 72 on GluR6 responses (6 oocytes, 1-2 batches of oocytes from different frogs for each compound).

Scheme 1

Synthesis of (E)-3-phenyl-2-styrylquinazolin-4(3H)-ones. (a) Ac₂O, reflux. (b) AcOH, reflux. (c) Ac₂O, AcOH, NaOAc, reflux.

Scheme 2

Suzuki route for synthesis of (E)-3-phenyl-2-styrylquinazolin-4(3H)-ones. (a) TBDMSCl, NMM, THF. (b) RB(OH)₂, Pd(PPh₃)₄, aq. NaHCO₃, 1,2-DME, reflux. (c) Ac₂O, AcOH, NaOAc, reflux.

Scheme 3

Synthesis of 81. (a) H₂, Pd/C, DMF.