NEW SPIROPIPERIDINES AS POTENT AND SELECTIVE NONPEPTIDE TACHYKININ NK2 RECEPTOR ANTAGONISTS

The synthesis of a series of 2-(5-fluoro-1H-indol-3-yl)ethyl spiropipe ridines is described together with their tachykinin NK2 receptor affin ities measured in a rat colon binding assay. Equivalent NK2 receptor b inding affinity was observed for the spirooxazolidinone l-3-yl)ethyl]- 1-oxa-3,8-diazaspiro[4,5]decan-2-one (3a), the imidazolidinone ndol-3- yl)ethyl]-1,3,8-triazaspiro[4,5]decan-2-one (3s), and the pyrrolidinon e H-indol-3-yl)ethyl]-2,8-diazaspiro[4,5]decan-3-one (3t). Substitutio n in the phenyl ring of compound 3a produced no significant enhancemen t in NK2 binding affinity. Replacement of the phenyl ring in 3a with o ther aromatic rings resulted in a significant loss in binding affinity . Compound 3a was shown to be a potent NK2 receptor antagonist in guin ea pig trachea where it also demonstrated 1000-fold selectivity for NK 2 receptors over NK1. In the anesthetized guinea pig, compound 3a admi nistered by the intravenous or oral route displayed potent and long-la sting antagonist activity against NK2 receptor agonist induced broncho constriction.