On the neuropharmacology of Harmane and other β-carbolines

Abstract

β-Carbolines have been recently proposed as candidates for the unknown endogenous ligand of the benzodiazepine receptor. Out of the β-carboline derivatives already found in the mammalian CNS, harmane is clearly the most potent inhibitor of benzodiazepine receptor binding. Therefore, it has been considered as possible endogenous ligand for this new receptor system. However, a certain degree of specificity might be a basic condition to accept the hypothesis of harmane as the endogenous ligand. Thus, the effects of harmane as well as other β-carbolines on several neurotransmitter receptor binding systems in vitro and on some neuropharmacological tests in vivo were investigated. Harmane developed the highest affinity towards the benzodiazepine binding site among all systems investigated. Its IC 50-values for inhibiting opiate and muscarinic cholinergic receptor binding were about four times lower than those for dopamine and serotonin receptor binding but were about four times higher than that found for the benzodiazepine receptor binding. Norharmane exerted a remarkable displacing activity only at the benzodiazepine binding site. Harmine affected mainly the opiate and cholinergic muscarinic system, whereas tetrahydronorharmane turned out to be a potent inhibitor of serotonin and dopamine receptor binding. Doses of harmane needed to produce convulsions as indication of its possible benzodiazepine receptor agonistic properties are also sufficient to diminish nociception and decrease body temperature whereas the apomorphine-induced licking rate was affected at higher doses. The data demonstrate that harmane affects not only the benzodiazepine binding site but also other neuronal mechanisms. Furthermore, only minor changes of the β-carboline structure lead to substantially different effects. Therefore, the search for other β-carbolines with higher affinity for the benzodiazepine binding site as harmane seems to be promising.