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Analysis of the structural requirements of compound 1 (SR48968), a potent NK2 receptor antagonist, revealed that the 4-phenyl group of the piperidine is essential for binding with the NK2 receptor and occupies an equatorial position. Energy calculation of a variety of substituted 4-phenyl piperidines revealed that spiro[isobenzofuran-1(3H),4'-piperidine] possesses a conformationally restricted equatorial phenyl group. Our compound 12 (YM-35375) possessing this spiro-substituted piperidine bound to the NK2 receptor with an IC50 value of 84 nM and to the NK1 receptor with an IC50 value of 710 nM. It showed more potent inhibitory activity (ID50 41 micrograms/kg (i.v.)) against [beta-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than (+/-)-SR48968 (ID50 68 micrograms/kg (i.v.)). YM-35375 may be a new lead compound for novel NK2 receptor antagonists or NK1-NK2 dual antagonists.

chemical and pharmaceutical bulletin/chemical and pharmaceutical bulletin

Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. I. Design and Synthesis of (.+-.)-N-(2-(3,4-Dichlorophenyl)-4-(spiro(isobenzofuran-1(3H),4'-piperidin)-1'-yl)butyl)-N-methylbenzamide, YM-35375, as a New Lead Compound for Novel Neurokinin Receptor Antagonists.