CNS 7056: a novel ultra-short-acting Benzodiazepine.
BACKGROUND
A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo.


METHODS
The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes (alpha1beta2gamma2, alpha2beta2gamma2, alpha3beta2gamma2, alpha5beta2gamma2) of the gamma-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test.


RESULTS
CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 mum) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil.


CONCLUSIONS
CNS 7065 is a high-affinity and selective ligand for the benzodiazepine site on the GABAA receptor. CNS 7056 does not show selectivity between GABAA receptor subtypes. CNS 7056 is a potent sedative in rodents with a short duration of action. Inhibition of substantia nigra pars reticulata firing and the inhibition of the effects of CNS 7056 by flumazenil show that it acts at the brain benzodiazepine receptor.
Kilpatrick
Gavin J
GJ
CeNeS Limited, Compass House, Cambridge CB4 9ZR, United Kingdom. gavin.kilpatrick@cenes.com
McIntyre
Margaret S
MS
Cox
Richard F
RF
Stafford
Jeffrey A
JA
Pacofsky
Gregory J
GJ
Lovell
Gwyer G
GG
Wiard
Robert P
RP
Feldman
Paul L
PL
Collins
Holly
H
Waszczak
Barbara L
BL
Tilbrook
Gary S
GS
D000818:Animals; D001569:Benzodiazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005445:Flunitrazepam / Q000493:pharmacokinetics; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008874:Midazolam / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects; D013552:Swine; D013556:Swine, Miniature; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D006993:Hypnotics and Sedatives; D007473:Ion Channels; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C522201:remimazolam; D008874:Midazolam