Subject(s)
Alkaloids/pharmacology , Carbolines/pharmacology , Central Nervous System/drug effects , Harmine/pharmacology , Indoles/pharmacology , Receptors, Drug/drug effects , Animals , Apomorphine/antagonists & inhibitors , Body Temperature/drug effects , Harmine/analogs & derivatives , Male , Pain/physiopathology , Rats , Receptors, Dopamine/drug effects , Receptors, GABA-A , Receptors, Muscarinic/drug effects , Receptors, Opioid/drug effects , Receptors, Serotonin/drug effectsABSTRACT
Harmane and other related beta-carbolines are putative endogenous ligands of the benzodiazepine receptor. Since the compounds are potent convulsants they may have agonist activities at the benzodiazepine receptor while the benzodiazepines may be antagonists. This hypothesis was proved by comparing the in vivo and in vitro antagonism of benzodiazepines by harmane and other beta-carbolines. Harmane is clearly a competitive inhibitor of benzodiazepine receptor binding in vitro. Moreover, harmane-induced convulsions can be inhibited reversibly by diazepam in a manner which is consistent with the assumption of competitive antagonism in vivo. For some beta-carboline derivatives a correlation was found between the affinity for the benzodiazepine receptor in vitro and the convulsive potency in vivo. Thus, the data reported suggest that harmane or other related beta-carbolines are putative endogenous agonists of the benzodiazepine receptor. This suggestion is further supported by the observation that diazepam is equally potent in inhibiting harmane- or picrotoxin-induced convulsions, indicating a convulsive mechanism within the GABA receptor-benzodiazepine receptor system.
Subject(s)
Alkaloids/pharmacology , Anti-Anxiety Agents/antagonists & inhibitors , Carbolines/pharmacology , Harmine/pharmacology , Indoles/pharmacology , Animals , Anti-Anxiety Agents/metabolism , Benzodiazepines , Brain/metabolism , Female , Glycine/metabolism , Harmine/analogs & derivatives , In Vitro Techniques , Rats , Receptors, Cell Surface/drug effects , Receptors, Drug/drug effects , Seizures/chemically induced , Spinal Cord/metabolism , Strychnine/metabolism , gamma-Aminobutyric Acid/metabolismABSTRACT
The interaction of several beta-carbolines with specific [3H]-flunitrazepam binding to benzodiazepine receptors in rat brain membranes was investigated. Out of the investigated compounds, harmane and norharmane were the most potent inhibitors of specific [3H]-flunitrazepam binding, with IC50-values in the micromolar range. All other derivatives, including harmine, harmaline, and several tetrahydroderivatives were at least ten times less potent. Harmane has been previously found in rat brain and human urine, so it is the most potent endogenous inhibitor of specific [3H]-flunitrazepam binding known so far, with a several fold higher affinity for the benzodiazepine receptor than inosine and hypoxanthine. Thus, we suggest that harmane or other related beta-carbolines could be potential candidates as endogenous ligands of the benzodiazepine receptor.
