Phosphodiesterase-IV inhibition, respiratory muscle relaxation and bronchodilation by WAY-PDA-641.

The ability of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (E)-O-(aminocarbonyl) oxime) (WAY-PDA-641) to inhibit cyclic AMP-metabolizing phosphodiesterases (PDEs) and to relax respiratory muscle was explored as part of a program to identify a PDE-IV inhibitor for potential use in the treatment of asthma. WAY-PDA-641 was identified as a preferential inhibitor of PDE-IV, possessing 36 times greater potency versus canine trachealis PDE-IV than PDE-III (IC50, 4.2 x 10(-7) M and 1.5 x 10(-5) M, respectively). The classification of WAY-PDA-641 as a preferential PDE-IV inhibitor was supported in radioligand binding studies, which demonstrated that 10 microM WAY-PDA-641 did not displace ligands from a large number of receptors, and in functional studies, which used isolated guinea pig tracheal rings. Under conditions in which tracheal rings were made sensitive to the relaxant effects of PDE-IV or PDE-III inhibitors, WAY-PDA-641 induced relaxation with IC50S of 2.6 x 10(-8) M (PDE-IV) and 3.2 x 10(-5) M (PDE-III). Moreover, PDE-IV inhibitory concentrations of WAY-PDA-641 significantly potentiated the relaxant effects of albuterol. WAY-PDA-641 reversed tracheal contractions induced by prostaglandin F2 alpha, leukotriene D4 or histamine in a biphasic manner consistent with its activity as a preferential PDE-IV inhibitor. The IC50S for reversal of each spasmogen were similar, which confirmed that WAY-PDA-641 is a functional antagonist of respiratory muscle contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Citation

R J Heaslip, L J Lombardo, J M Golankiewicz, B A Ilsemann, D Y Evans, B D Sickels, J K Mudrick, J Bagli, B M Weichman. Phosphodiesterase-IV inhibition, respiratory muscle relaxation and bronchodilation by WAY-PDA-641. The Journal of pharmacology and experimental therapeutics. 1994 Feb;268(2):888-96

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PMID: 8114002

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