Synthesis of beta-carboline-benzodiazepine hybrid molecules: use of the known structural requirements for benzodiazepine and beta-carboline binding in designing a novel, high-affinity ligand for the benzodiazepine receptor.
Hybrid molecules incorporating pharmacologically important structural features of both 3-carboxy-beta-carbolines and 1,4-benzodiazepines were synthesized, and their affinities for the benzodiazepine receptor were determined in vitro. One of these hybrids, 8,14-dioxo-13,14-dihydro-8H-indolo[3',2':4,5]pyrido[2,1-c] [1,4]benzodiazepine (13), demonstrated high affinity for the receptor, displacing both benzodiazepines (IC50 = 23 nM) and beta-carbolines (IC50 = 47 nM) from their binding sites. Of the compounds synthesized, 13 also most closely satisfied the structural requirements that generally ensure a high affinity of both beta-carbolines and benzodiazepines for the receptor (e.g., aromaticity of the beta-carboline, presence of a carbonyl at C-3 of the beta-carboline and of a pi 2-region on the benzodiazepine). The hybrids not fulfilling these requirements had no affinity for the receptor. In vivo pharmacological properties of 13 could not be demonstrated because of its metabolic instability and/or its poor transport into the brain. The results are discussed in terms of a possible overlapping of beta-carboline binding sites with those of benzodiazepines on the receptor.
D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis*; D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D011963:Receptors, GABA-A / Q000378:metabolism*
D002243:Carbolines; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005445:Flunitrazepam; C024915:beta-carboline-3-carboxylic acid ethyl ester