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Most drugs are bound to human serum albumin (HSA) via a few high affinity binding sites and several sites of much lower affinity. There is now increasing evidence that the actual number of high affinity drug-binding sites of HSA is rather small. Thus, each of these binding sites binds several drugs of very different chemical and pharmacological properties with relative high affinity. On the other hand these drug-binding sites can in some cases be very specific and even stereoselective, as demonstrated by the stereospecific binding of drugs to some of these binding sites. The discrepancy between both observations can be explained by the conformational adaptability of the HSA-binding sites.

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.

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