Synthesis and benzodiazepine receptor affinity of N-(indol-3-ylglyoxylyl)-dipeptide derivatives. Structural requirements for inverse agonist/antagonist receptor interactions.

Several N-(indol-3-ylglyoxylyl)dipeptide derivatives 1-12 were synthesized and tested for their affinity at the benzodiazepine receptor in bovine cortical membranes. They proved to bind with low or no affinity at the receptor site. It was hypothesized that this result was not due to the steric hindrance of the dipeptide side chain, but to the establishment of intramolecular hydrogen bonds involving the indole N-H and/or the glyoxylyl C = O(2). Conformational analysis indicated that coiled conformations, with intramolecular hydrogen bonds, were energetically more favoured than the staggered, completely unfolded ones. Therefore, the low or no affinity of these compounds should be attributed to the unavailability of the N-H and/or C = O(2) groups for the binding, again confirming that both these groups are necessary for interaction with the receptor.