Conformationally Restricted Tricyclic Antidepressants. 1. Octahydrodibenzazepinonaphthyridines as Rigid Imipramine Analogues

Article abstract of DOI:10.1021/jm00182a011

The stereoselective synthesis and structure elucidation of the racemic 2-methyl-1,2,3,4,4a,8,9,15a-octahydro-15H-dibenzazepino<5,4a,4-bc>-2,7-naphthyridine ring-fusion isomers (1a and 1b) are described.Photocyclization of N-(1-methyl-1,2,5,6-tetrahydronicotinyl)-10,11-dihydro-5H-dibenzazepine (3) in methanol vs. tetrahydrofuran stereoselectively gave, respectively, the cis (moderate yield) or the trans (poor yield) pentacyclic lactams (4a or 4b).Equilibration of 4a in base gave a 1:2 mixture of 4a and 4b, which was separated by column chromatography.Borane reductions of 4a and 4b gave 1a and 1b without epimerization.The racemic ring-fusion isomers were compared with imipramine in rodents as inhibitors of (-)-norepinephrine uptake in vitro and in vivo, as inhibitors of serotonin uptake in vitro, and as inhibitors of the binding of the muscarinic cholinergic antagonist <³H>quinuclidinylbenzilate (QNB), the α-adrenergic antagonist <<<2-(2',6'-<³H>dimethoxyphenoxy)ethyl>amino>methyl>benzodioxane (WB 4101), and the dopaminergic antagonist <³H>spiperone at their respective membrane binding sites in homogenates obtained from rat brain.Both 1a and 1b inhibited (-)-norepinephrine uptake in a rat brain synaptosomal preparation; 1b was slightly more potent than 1a but somewhat less potent than imipramine.Imipramine was more than twice as effective as 1b as an inhibitor of the neuronal uptake of the norepinephrine synthesis inhibitor 4,α-dimethyl-m-tyramine (H77/77) in vivo, while 1a appeared to potentiate rather than prevent the norepinephrine depleting action of H77/77.Both 1a and 1b were virtually inactive as inhibitors of synaptosomal serotonin uptake.Imipramine and 1b were nearly equipotent as inhibitors of <³H>QNB binding and significantly more active than 1b.In the <³H>spiperone binding assay, 1a was comparable to chlorpromazine in potency.Imipramine and 1b were much less effective.The amine uptake and receptor binding results are rationalized on the basis of conformational structure-activity relationships.