ABSTRACT
Positive modulators at the benzodiazepine site of α2- and α3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABA(A) receptors and that show no functional activity at α1-containing GABA(A) receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABA(A) receptors, while simultaneously neutral antagonists at α1-containing GABA(A) receptors, is described. Such functionally selective modulators of GABA(A) receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.
Subject(s)
Receptors, GABA-A/chemistry , Allosteric Regulation , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Benzodiazepines/chemistry , GABA-A Receptor Antagonists/chemical synthesis , GABA-A Receptor Antagonists/chemistry , GABA-A Receptor Antagonists/pharmacology , Heterocyclic Compounds, 2-Ring/chemistry , Quinolines/chemistry , Receptors, GABA-A/metabolism , Structure-Activity RelationshipABSTRACT
A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.
Subject(s)
Analgesics/chemical synthesis , Pain/drug therapy , Peripheral Nervous System Diseases/drug therapy , Pyridazines/chemical synthesis , Quinolines/chemical synthesis , Receptors, Glycine/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Administration, Oral , Alkynes/chemical synthesis , Alkynes/chemistry , Alkynes/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Brain/metabolism , Chronic Disease , Constriction, Pathologic/complications , Male , Pain/etiology , Peripheral Nervous System Diseases/etiology , Pyridazines/chemistry , Pyridazines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Sciatic Nerve/pathology , Structure-Activity RelationshipABSTRACT
Several members of the 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones (2) have been identified as being potent and selective NMDA glycine-site antagonists. Increasing size of the alkyl substituent on the alpha-carbon led to a progressive decrease in binding affinity. Some of these analogues possess improved drug-like properties such as cellular permeability, solubility and oral absorption.