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Intestinal activation of a new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative, in rats.

5-[(2- Aminoacetamide)methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl]- N,N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S) is a newly synthesized sleep inducer, which itself has negligible affinities for benzodiazepine receptors. However, several active metabolites have been found in rat plasma. In this paper, the mechanisms and contribution of the activation of 450191-S in rat small intestine were investigated. When 450191-S was incubated with rat everted small intestine, desglycylated 450191-S (191 DG) was released in the medium and subsequently converted to 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-1). The results obtained using synthetic 191DG indicated that the conversion of 191DG to M-1 was spontaneous and very rapid, with a half-life of 9 min in pH 7.4 buffer. After incubation, the intestinal tissue contained a small amount of unchanged 450191-S but large amounts of 191DG and/or M-1. Next, metabolites in the mesenteric blood were determined following instillation of 14C-450191-S into a segment of rat ileum and it was found that almost all of the radioactivity in the blood was accounted for by 191DG and/or M-1. In conclusion, 450191-S is metabolized by intestinal aminopeptidases to 191DG, which is spontaneously converted to M-1, an active metabolite, and the activation is completed by a single passage through the intestinal wall.