Identification of 3,5-Dihydro-2-aryl-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-diones as Novel High-Affinity Glycine Site N-Methyl-D-aspartate Antagonists

• Published in: Journal of medicinal chemistry Vol. 38; no. 12; pp. 2239 - 2243
• Main Authors: MacLeod, Angus M, Grimwood, Sarah, Barton, Cheryl, Bristow, Linda, Saywell, Kay L, Marshall, George R, Ball, Richard G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.06.1995; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Cerebral Cortex - drug effects; Cerebral Cortex - physiology; Chemistry, Medicinal; Female; glycine; Glycine - metabolism; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Membrane Potentials - drug effects; Mice; Mice, Inbred DBA; Neuropharmacology; Neuroprotective agent; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quinolines - chemistry; Quinolines - metabolism; Quinolines - pharmacology; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - chemistry; Science & Technology; NMDA RECEPTOR; POTENT; ACID; DERIVATIVES; BINDING; Nitrogen heterocycle; Rodentia; Anticonvulsant; Neuroprotective agent; Glutamate receptor; Tricyclic compound; Route of administration; Vertebrata; Mammalia; Structure activity relation; Mouse; Intracerebral administration; Affinity; Aromatic compound; Antagonist; NMDA receptor; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00012a024

Almost all of the exisiting known antagonists at the glycine site of the N-methyl-D-aspartate (NMDA) receptor have a low propensity for crossing the blood-brain barrier. It has been suggested that in many cases this may be due to the presence of a carboxylic acid which is a common feature of most of the potent full antagonists at this receptor. In this study, 2-aryl-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-diones were found to have high-affinity binding at the glycine receptor. In particular, structure-activity studies identified 7-chloro-3,5-dihydro-2(4-methoxyphenyl)-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione as the most potent of a series of analogues with an IC50 of 3.3 nM. The measured pK(a) values in this class of compounds (typically 4.0) indicate they are of equivalent acidity to carboxylic acids. Functional antagonism was demonstrated by inhibition of NMDA-evoked responses in rat cortical slices. Anticonvulsant activity in DBA/2 mice was achieved after dosing by direct injection into the cerebral ventricles, but no activity was seen after systemic administration, suggesting low brain penetration with this class of antagonists.