Synthetic routes to 4-amino-3-carboxy-beta-carboline derivatives: incidental formation of novel furo[3,4-c]-beta-carbolin-2-ones displaying high affinities for the benzodiazepine receptor.
The synthesis of the first 4-amino-3-carboxy-beta-carboline derivative (35) is described. This synthesis is based on ozonolysis of the 4-vinyl-beta-carboline-3-carboxamide 17 to give the 4-aldehyde 20 and potassium permanganate oxidation of the latter to the 4-carboxylic acid 34 followed by a DPPA-promoted Curtius rearrangement. During the course of these transformations, a number of furo[3,4-c]-beta-carbolin-2-ones, differing in substituents at the C-10 position, were formed. While these beta-carboline lactones (15,25,26,33) generally displayed good affinities for the central type benzodiazepine receptor in vitro (IC50's in the 10-50 nM range), one compound, 29, demonstrated an exceptionally high binding affinity (IC50 = 0.2 nM). Compound 29 was shown in electrophysiological and behavioral studies to act as a benzodiazepine receptor antagonist. The unusually high binding affinity of compound 29 corroborates the hypothesis that the benzodiazepine receptor preferentially recognizes the C-3 carbonyl function of 3-carboxy-beta-carbolines in an s-cis conformation (i.e., the carbonyl oxygen on the same side as the pyridinyl nitrogen).
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France.
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D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002642:Chick Embryo; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism*; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002243:Carbolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid