3-Phenyl-Substituted Imidazo[1,5-a]quinoxalin-4-ones and Imidazo[1,5-a]quinoxaline Ureas That Have High Affinity at the GABAA/Benzodiazepine Receptor Complex

• Published in: Journal of medicinal chemistry Vol. 39; no. 19; pp. 3820 - 3836
• Main Authors: Jacobsen, E. Jon, Stelzer, Lindsay S, Belonga, Kenneth L, Carter, Donald B, Im, Wha Bin, Sethy, Vimala H, Tang, Andrew H, VonVoigtlander, Philip F, Petke, James D
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 13.09.1996
• Subjects: Animals; Anticonvulsants; Benzodiazepines - antagonists & inhibitors; Biological and medical sciences; Cell Membrane - metabolism; Cerebral Cortex - metabolism; Drug Synergism; Ethanol - pharmacology; Gabaergic and benzodiazepinic system; Imidazoles - chemical synthesis; Imidazoles - metabolism; Imidazoles - therapeutic use; Ligands; Male; Medical sciences; Mice; Molecular Conformation; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pentylenetetrazole - antagonists & inhibitors; Pharmacology. Drug treatments; Quinoxalines - chemical synthesis; Quinoxalines - metabolism; Quinoxalines - therapeutic use; Rats; Receptors, GABA - metabolism; Seizures - chemically induced; Seizures - prevention & control; Structure-Activity Relationship; Substance-Related Disorders; Rat; Angular nitrogen heterocycle; Ligand; Central nervous system; Lactam; Anticonvulsant; Benzodiazepine receptor; Organic carbamate; Modeling; Structure activity relation; Molecular model; Force field method; Ureas; Aromatic compound; Chemical synthesis; Rodentia; Tricyclic compound; In vivo; Vertebrata; Biological fixation; Mammalia; Mouse; Animal; Affinity; Gabaergic receptor A; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960070+

A series of imidazo[1,5-a]quinoxalin-4-ones and imidazo[1,5-a]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-a]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, although most analogs were partial agonists as indicated by [35S]TBPS and Cl- current ratios. Interestingly, a subseries of piperazine ureas was identified which had biphasic efficacy, becoming more antagonistic with increasing concentration. Analogs within the imidazo[1,5-a]quinoxalin-4-one series had substantially decreased binding affinity as compared to the quinoxaline urea series. These compounds ranged from antagonists to full agonists by in vitro analysis, with several derivatives having roughly 4-fold greater intrinsic activity than diazepam as indicated by Cl- current measurement. Numerous compounds from both series were effective in antagonizing metrazole-induced seizures, consistent with anticonvulsant properties and possible anxiolytic activity. Most of the quinoxaline ureas and quinoxalin-4-ones were active in an acute electroshock physical dependence side effect assay in mice precluding further development.