New Spiropiperidines as Potent and Selective Non-Peptide Tachykinin NK2 Receptor Antagonists

Article abstract of DOI:10.1021/jm00019a006

The synthesis of a series of 2-(5-fluoro-1H-indol-3-yl)ethyl spiropiperidines is described together with their tachykinin NK₂ receptor affinities measured in a rat colon binding assay.Equivalent NK₂ receptor binding affinity was observed for the spirooxalidinone 3-benzyl-8-<2-(5-fluoro-1H-indol-3-yl)ethyl>-1-oxa-3,8-diazaspiro<4.5>decan-2-one (3a), the imidazolidinone 3-benzyl-8-<2-(5-fluoro-1H-indol-3-yl)ethyl>-1,3,8-triazaspiro<4.5>decan-2-one (3s), and the pyrrolidinone 2-benzyl-8-<2-(5-fluoro-1H-indol-3-yl)ethyl>-2,8-diazaspiro<4.5>decan-3-one (3t).Substitution in the phenyl ring of compound 3a produced no significant enhancement in NK₂ binding affinity.Replacement of the phenyl ring in 3a with other aromatic rings resulted in a significant loss in binding affinity.Compound 3a was shown to be a potent NK₂ receptor antagonist in guinea pig trachea where it also demonstrated 1000-fold selectivity for NK₂ receptors over NK₁.In the anesthesized guinea pig, compound 3a administered by the intravenous or oral route displayed potent and long-lasting antagonist activity against NK₂ receptor agonist induced bronchoconstriction.