High-affinity partial agonist imidazo[1,5-a]quinoxaline amides, carbamates, and ureas at the gamma-aminobutyric acid A/benzodiazepine receptor complex

E J Jacobsen; R E TenBrink; L S Stelzer; K L Belonga; D B Carter; H K Im; W B Im; V H Sethy; A H Tang; P F VonVoigtlander; J D Petke

doi:10.1021/jm940765f

High-affinity partial agonist imidazo[1,5-a]quinoxaline amides, carbamates, and ureas at the gamma-aminobutyric acid A/benzodiazepine receptor complex

J Med Chem. 1996 Jan 5;39(1):158-75. doi: 10.1021/jm940765f.

Authors

E J Jacobsen¹, R E TenBrink, L S Stelzer, K L Belonga, D B Carter, H K Im, W B Im, V H Sethy, A H Tang, P F VonVoigtlander, J D Petke

Affiliation

¹ Department of Medicinal Chemistry, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.

PMID: 8568803
DOI: 10.1021/jm940765f

Abstract

A series of imidazo[1,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the gamma-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying efficacies ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Many of these compounds were also effective in antagonizing metrazole-induced seizures in accordance with anticonvulsant and possible anxiolytic activity. Selected quinoxalines displayed limited benzodiazepine-type side effects such as ethanol potentiation and physical dependence in animal models. Dimethylamino urea 41 emerged as the most interesting analog, having a partial agonist profile in vitro while possessing useful activity in animal models of anxiety such as the Vogel and Geller assays. In accordance with its partial agonist profile, 41 was devoid of typical benzodiazepine side effects.

MeSH terms

Animals
Anxiety / drug therapy
Benzodiazepines / pharmacology
Binding, Competitive
Brain / drug effects
Brain / metabolism
Bridged Bicyclo Compounds, Heterocyclic / antagonists & inhibitors
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Chlorides / metabolism
Flunitrazepam / antagonists & inhibitors
Flunitrazepam / metabolism
GABA Agonists / chemical synthesis*
GABA Agonists / chemistry
GABA Agonists / pharmacology*
GABA Antagonists / pharmacology
Molecular Conformation
Molecular Structure
Oxadiazoles / chemical synthesis*
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Pentylenetetrazole / pharmacology
Quinoxalines / chemical synthesis*
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Rats
Receptors, GABA-A / metabolism*

Substances

3--(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-((dimethylamino)carbonyl)-4,5-dihydroimidazo(1,5-a)quinoxaline
Bridged Bicyclo Compounds, Heterocyclic
Chlorides
GABA Agonists
GABA Antagonists
Oxadiazoles
Quinoxalines
Receptors, GABA-A
Benzodiazepines
Flunitrazepam
tert-butylbicyclophosphorothionate
Pentylenetetrazole