3-NITRO-3,4-DIHYDRO-2(1H)-QUINOLONES - EXCITATORY AMINO-ACID ANTAGONISTS ACTING AT GLYCINE-SITE NMDA AND LPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTORS

3,4-Dihydro-2(1H)-quinolones, evolved from 2-carboxy-1,2,3,4-tetrahydr oquinolines and 3-carboxy-4-hydroxy-2(1H)-quinolones, have been synthe sized and evaluated in vitro for antagonist activity at the glycine si te on the NMDA receptor and for AMPA lpha-amino-3-hydroxy-5-methyl-4-i soxazolepropionic acid] antagonist activity. Generally poor potency at the glycine site is observed when a variety of electron-withdrawing s ubstituents are attached to the 3-position of 3,4-dihydro-2(1H)-quinol ones. The analogues 5-9 (IC50 values > 100 muM, Table 1) exist largely in the 3,4-dipseudoaxial conformation (as evidenced by H-1 NMR spectr a), whereas the 3-cyano derivative (10, IC50 = 12.0 muM) has a relativ ely high population of the 3-pseudoequatorial conformer. The 3-nitro a nalogue (4, IC50 = 1.32 muM) has a pK(a) almost-equal-to 5 and thus ex ists at physiological pH as an anion with the nitro group planar to th e quinolone ring. The general requirement of acidity for high affinity binding at the glycine/NMDA site is supported with the good activity of the other 3-nitro derivatives (13-21), all of which are deprotonate d at physiological pH. The 3-nitro-3,4-dihydro-2(1H)-quinolones and 2- carboxy-1,2,3,4-tetrahydroquinolines show quite different structure-ac tivity relationships at the 4-position. The unselective excitatory ami no acid activity of 21 is comparable with 6,7-dichloro-quinoxaline-2,3 -dione and 6,7-dichloroquinoxalic acid and this suggests similarities in their modes of binding to excitatory amino acid receptors. The broa d spectrum excitatory amino acid antagonist activity of the 4-unsubsti tuted analogue 21 (K(b) NMDA = 6.7 muM, K(b) AMPA = 9.2 muM) and the g lycine/NMDA selectivity of the other 3-nitro derivatives allows the pr oposal of a model for AMPA receptor binding which differs from the gly cine binding pharmacophore in that there is bulk intolerance adjacent to the 4-position. Compound 21 (L-698,544) is active (ED50 = 13.2 mg/k g) in the DBA/2 mouse anticonvulsant model and is the most potent comb ined glycine/NMDA-AMPA antagonist yet reported, in vivo, and may prove to be a useful pharmacological tool.