Muscarinic receptors and urinary bladder selectivity : Properties that determine the organ selectivity of compounds

Sammanfattning: Urinary bladder contraction is mainly mediated by activation of muscarinic acetylcholine receptors (mAChR). Muscarinic antagonists are often effective in treatment of unstable bladder. The effectiveness of this treatment has often been limited by side effects as dry mouth. In this thesis, various properties that could confer bladder selectivity to antimuscarinic compounds were investigated.In the search for compounds with tissue selectivity a series of quinuclidine derivatives (about 100) were tested. None of these displayed any muscarinic agonist activity in the isolated guinea pig urinary bladder but behaved as antagonists. About 15 of the compounds showed binding affinities less than Ki 10 nM to mAChR in guinea pig tissues.None of these potent derivatives displayed any tissue selectivity.There are 5 mAChR subtypes, M1-M5. Urinary bladder contraction is generally believed to be mediated by the M3 subtype. Effects on urinary bladder contraction and on salivation of muscarinic antagonists with different receptor selectivity profiles were studied in vivo in the anaesthetised cat. It was possible to obtain selectivity for bladder contraction over salivation in vivo. This functional selectivity was not favoured by selectivity for M3 receptors over M2.The relative importance of mAChR subtypes for mediating contraction of urinary bladder in vitro and in vivo was different. M3 was most important in vitro while M2 and to a minor degree M1 mediated bladder contraction in vivo. This was found by applying multivariate analysis (PLS) on previously published data.The relative importance of M2 and M3 receptors for mediating contraction induced with submaximal and supramaximal concentration of agonist was investigated in the isolated guinea pig bladder. The relative contribution of M2 to contraction was higher at a submaximal than at a supramaximal concentration of agonist.In conclusion, cholinergic control of urinary bladder contraction is not exclusively mediated by muscarinic M3 receptors, also the M2 subtype seems to be of importance.