1025915-20-1Relevant articles and documents
New Spiropiperidines as Potent and Selective Non-Peptide Tachykinin NK2 Receptor Antagonists
Smith, Paul W.,Cooper, Anthony W. J.,Bell, Richard,Beresford, Isabel J. M.,Gore, Paul M.,et al.
, p. 3772 - 3779 (2007/10/03)
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--1-oxa-3,8-diazaspirodecan-2-one (3a), the imidazolidinone 3-benzyl-8--1,3,8-triazaspirodecan-2-one (3s), and the pyrrolidinone 2-benzyl-8--2,8-diazaspirodecan-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.
