Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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)
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PMID:Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors. 197 Mar 61

Development of novel antiepileptic drugs (AEDs) requires determining the margin between the desired anticonvulsant effect and undesired adverse effects (AE) (therapeutic index). For this purpose, drug-induced "minimal neurological deficits" (e.g., motor dysfunctions) are commonly quantified by simple tests, such as the rotarod test, in normal, i.e., nonepileptic animals. However, increasing evidence shows that chronic brain dysfunction associated with epilepsy may increase susceptibility to the AE of certain AEDs, e.g., N-methyl-D-aspartate (NMDA) receptor antagonists. The increased AE potential of such investigational drugs can be predicted by using kindled rats instead of normal rodents in preclinical drug evaluation studies. In the present experiments, we wished to determine whether kindled rats also exhibit an altered susceptibility to neurological adverse effects of standard AEDs, i.e., carbamazepine (CBZ), phenobarbital (PB), valproate (VPA), and diazepam (DZP). Abecarnil, a novel benzodiazepine (BZD) receptor agonist, was included in the study for comparison. All drugs were administered in diverse doses in kindled and nonkindled rats, and all behavioral alterations were scored in the cage and open field. Furthermore, the rotarod test was used to detect and quantify motor impairment induced by drug treatments. Kindled rats were more susceptible than nonkindled rats to motor impairment (ataxia and/or rotarod failures) induced by high doses of AEDs, although differences were noted between the drugs tested. VPA was the only drug that induced stereotyped behavior; it was much more potent in this respect in kindled than nonkindled rats. Abecarnil did not differ substantially in its AE in either subgroup of animals. Our data indicate that epileptogenesis induced by kindling renders the brain more susceptible to certain AE of AEDs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kindling increases the sensitivity of rats to adverse effects of certain antiepileptic drugs. 763 95