Open AccessAntimuscarinic Potency and Bladder Selectivity of PNU‐200577, a Major Metabolite of Tolterodine
Author(s) -
Nilvebrant Lisbeth,
Gillberg PerGöran,
Sparf Bengt
Publication year - 1997
Publication title -
pharmacology & toxicology
Language(s) - English
Resource type - Journals
eISSN - 1600-0773
pISSN - 0901-9928
DOI - 10.1111/j.1600-0773.1997.tb02064.x
Subject(s) - tolterodine , muscarinic acetylcholine receptor , potency , chemistry , pharmacology , overactive bladder , metabolite , in vivo , muscarinic acetylcholine receptor m3 , receptor , endocrinology , in vitro , biology , medicine , biochemistry , alternative medicine , microbiology and biotechnology , pathology
PNU‐200577 (labcode DD 01 [(R)‐N,N‐diisopropyl‐3‐(2‐hydroxy‐5‐hydroxymethylphenyl)‐3‐phenylpropanamine) is a major pharmacologically active metabolite of tolterodine, a new muscarinic receptor antagonist intended for the treatment of an overactive bladder. In virro , PNU‐200577 produced a competitive and concentration‐dependent inhibition of carbachol‐induced contraction of guinea‐pig isolated urinary bladder strips (K B =0.84 nM; pA 2 =9. 14). In vivo , PNU‐200577 was significantly more potent at inhibiting acetylcholine‐induced urinary bladder contraction than electrically induced salivation in the anaesthetised cat (ID 50 15 and 40 nmol. kg −l , respectively; P<0.0l). In radioligand binding studies carried out in homogenates of guinea‐pig tissues and Chinese hamster ovary cell lines expressing human muscarinic ml‐m5 receptors, PNU‐200577 was not selective for any muscarinic receptor subtype. Thus, PNU‐200577 is similar to tolterodine in terms of antimuscarinic potency, functional selectivity for the urinary bladder in vivo and absence of selectivity for muscarinic receptor subtypes in vitro . The results of this study clearly indicate that PNU‐200577 contributes to the therapeutic action of tolterodine, in view of its high antimuscarinlc potency, similar serum concentration and lower degree of protein binding.