Synthesis and benzodiazepine receptor affinities of rigid analogues of 3-carboxy-beta-carbolines: demonstration that the benzodiazepine receptor recognizes preferentially the s-cis conformation of the 3-carboxy group.

摘要: 1H-Indolo[3',2':4,5]pyrido[3,2-b]-2-penten-5-olide (6) and 1H,5H-indolo[3',2'-c]-6,7-dihydro-2-pyridone (7), rigid analogues of methyl 4-ethyl-beta-carboline-3-carboxylate (8) N-methyl-4-ethyl-beta-carboline-3-carboxamide (9), respectively, were synthesized their in vitro binding affinities to the central type benzodiazepine receptors compared. The IC50 values 6 8 approximately equivalent (42 27 nM, respectively). amide derivative 9, for which theoretical energy calculations indicate that s-trans carbonyl conformation is preferred one, displayed very low affinity (IC50 greater than 10(4) nM). However, when group 9 was forced adopt s-cis as lactam 7, receptor largely restored = 150 nM), indicating carboxy at C-3 beta-carbolines preferentially recognized by this receptor. In vivo, compound showed neither convulsant, proconvulsant, nor anticonvulsant activity mice. Moreover, did not antagonize beta-carboline-3-carboxylate induced convulsions This lack attributed its inability cross blood-brain barrier since no significant displacement [3H]Ro 15-1788 from mouse brain could be observed vivo.