3-Ethoxy-beta-carboline: a high affinity benzodiazepine receptor ligand with partial inverse agonist properties.
3-Ethoxy-beta-carboline binds with high affinity to benzodiazepine receptors in the central nervous system (Ki approximately equal to 10.1, 15.3, and 25.3 nM in rat cerebellum, cerebral cortex, and hippocampus, respectively). This compound has pharmacological actions reminiscent of benzodiazepine receptor partial inverse agonists such as FG 7142 and 3-carboethoxy-beta-carboline. Thus, while not a convulsant, 3-ethoxy-beta-carboline potentiated the convulsant actions of pentylenetetrazole in mice. Furthermore, this compound reduced both the time spent and the total entries in the open arms of an elevated plus maze and also inhibited stress-induced ulcer formation, effects that are also observed with benzodiazepine receptor inverse agonists. These findings suggest that 3-ethoxy-beta-carboline is a partial inverse agonist at benzodiazepine receptors which may prove useful for in vivo studies since it has a higher affinity for benzodiazepine receptors and better solubility than the commonly used partial inverse agonist FG 7142. Furthermore, 3-ethoxy-beta-carboline appears to be less vulnerable to metabolic degradation than ester analogs with a similar pharmacological profile such as 3-carboethoxy-beta-carboline.
Trullas
R
R
Laboratory of Neuroscience, NIDDK, Bethesda, MD 20892.
Ginter
H
H
Jackson
B
B
Skolnick
P
P
Allen
M S
MS
Hagen
T J
TJ
Cook
J M
JM
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D004357:Drug Synergism; D005442:Flumazenil / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D010437:Peptic Ulcer / Q000503:physiopathology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced; D012995:Solubility; D013315:Stress, Psychological / Q000503:physiopathology
D002243:Carbolines; D003292:Convulsants; D008024:Ligands; D011963:Receptors, GABA-A; D005442:Flumazenil; C035874:FG 7142; C057378:3-ethoxy-beta-carboline