Spiro-substituted piperidines as neurokinin receptor antagonists. II. Syntheses and NK2 receptor-antagonistic activities of N-[2-aryl-4-(spiro- substituted piperidin-1'-yl)butyl]carboxamides

Article abstract of DOI:10.1248/cpb.46.242

In the course of our research on spiro-compounds as neurokinin receptor antagonists, N-[2-aryl-4-spiro-substituted piperidin-1'-yl)butyl]carboxamides were designed, based on YM-35375 (3) as a lead compound, and evaluated for NK₂ receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK₂ receptor with IC₅₀ values at the level of 10^-9. Among these compounds, (±)-1'-[4-(N-benzoyl-N-methylamino)- 3-(3,4-dichlorophenyl)butyl]spiro[benzo[c]thiophene-1(3H), 4'-piperidine] 2- oxide (58, YM-38336) showed 10 times more potent NK₂ receptor binding affinity than compound 3 (IC₅₀ values of 8.9 and 84nM, respectively). It showed more potent inhibitory activity (ID₅₀ 20μg/kg (i.v.)) against [β- Ala⁸]-NKA(4 - 10)-induced bronchoconstriction in guinea pigs than compound 3 (ID₅₀ 41 μg/kg (i.v.)). This compound was also effective intraduodenally in the same model, exhibiting an ID₅₀ value of 0.41 μg/kg.

Full text of DOI:10.1248/cpb.46.242

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