Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors.
Abecarnil (isopropyl 6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a novel ligand for central benzodiazepine (BZ) receptors, possessing anxiolytic and anticonvulsant properties, but with considerably reduced muscle relaxant effects in comparison to diazepam (DZP). In vitro, abecarnil inhibited the binding of the BZ [3H]lormetazepam to rat cerebral cortex membranes with an IC50 value of 0.82 nM in comparison to 56 nM for DZP. The ability of abecarnil to displace [3H]lormetazepam was enhanced 1.24-fold in the presence of 30 microM gamma-aminobutyric acid; the corresponding value for DZP was 2.8-fold. DZP and abecarnil were equally effective in enhancing the binding of t-[35S]butylbicyclophosphorothionate to rat cortical membranes. In vivo, abecarnil exhibited a 3- to 6-fold higher affinity to forebrain BZ receptors than DZP. Abecarnil was from 2 to 10 times more potent than DZP in most rodent tests of anxiolytic activity, and in reducing locomotor activity in mice and rats thoroughly habituated to the test chamber. However, in rats newly exposed to a novel cage, abecarnil was less potent than DZP in reducing locomotor activity. In tests of motor coordination, abecarnil, in contrast to DZP, showed no or only weak activity, and in potentiating the effects of ethanol and hexobarbital on motor performance abecarnil was 4 to 25 times less potent than DZP. Abecarnil antagonized the effects of BZs in the chimney and loss of righting reflex tests, but not in the rotarod test.(ABSTRACT TRUNCATED AT 250 WORDS)
Stephens
D N
DN
Research Laboratories of Schering AG, Berlin/West, Federal Republic of Germany.
Schneider
H H
HH
Kehr
W
W
Andrews
J S
JS
Rettig
K J
KJ
Turski
L
L
Schmiechen
R
R
Turner
J D
JD
Jensen
L H
LH
Petersen
E N
EN
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines / Q000378:metabolism / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D008140:Lorazepam / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011678:Punishment; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D014151:Anti-Anxiety Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C037476:tert-butylbicyclophosphorothionate; C023842:lormetazepam; C062769:abecarnil; D008140:Lorazepam; D003975:Diazepam