Characterization of novel ligands for wild-type and natural mutant diazepam-insensitive benzodiazepine receptors

Eur J Pharmacol. 1995 Apr 28;289(2):335-42. doi: 10.1016/0922-4106(95)90111-6.


A series of benzodiazepine receptor ligands with different chemical structures were evaluated for their affinities at diazepam-sensitive and diazepam-insensitive binding sites for [3H]Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5a][1,4] benzodiazepine-3-carboxylate) in cerebellar GABAA receptors. Rats of Wistar strain and of alcohol-sensitive (ANT) and alcohol-insensitive (AT) lines were used. The ANT rats possess a single point mutation in their GABAA receptor alpha 6 subunit, which makes their diazepam-insensitive sites sensitive to benzodiazepine agonists, unlike those of AT and Wistar rats. All compounds evaluated displayed high-affinity binding to diazepam-sensitive sites (Ki < 50 nM). In contrast, a wider range of affinities were observed at diazepam-insensitive sites which depended upon the basic structure and substitutions. The 7- and 8-halogen substituted imidazobenzodiazepines and 12-halogen substituted diimidazoquinazolines displayed the highest affinities (Ki < 15 nM), while intermediate to low affinities (100 < Ki < 4000 nM) were displayed by imidazoquinazolines, thienopyrimidines, one oxoimidazoquinoxaline, and some cyclopyrrolones. The imidazoquinoxalines evaluated displayed the lowest affinity (Ki > 10000 nM). The oxoimidazoquinoxaline, 6-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-5-isop ropyl-4-oxo-imidazo[1,5-a]quinoxaline (NNC 14-0578) and suriclone represent the first benzodiazepine receptor full agonists to bind with relatively high affinity (Ki approximately 100 nM) to diazepam-insensitive sites. The 5 position substituted methoxybenzyl, dimethylallyl, and 4-fluorobenzyl oxoimidazoquinoxaline analogs demonstrated a 58-336-fold higher affinity for ANT than AT diazepam-insensitive sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azides / pharmacology
  • Benzodiazepines / pharmacology
  • Binding, Competitive
  • Cerebellum / drug effects*
  • Diazepam / pharmacology*
  • Ethanol
  • Male
  • Mutation
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / chemistry*
  • Receptors, GABA-A / drug effects


  • Azides
  • Receptors, GABA-A
  • Benzodiazepines
  • Ethanol
  • Ro 15-4513
  • Diazepam