Relationship between Stereochemistry and the β3-Adrenoceptor Agonistic Activity of 4‘-Hydroxynorephedrine Derivative as an Agent for Treatment of Frequent Urination and Urinary Incontinence

This report proposes a beta(3)-adrenoceptor (AR) selective agonist, 2-[2-chloro-4-(2-([(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino)ethyl)phenoxy]acetic acid (1a), as a novel agent for treating urinary bladder dysfunction. This compound and its relatives have a unique feature among beta(3)-AR agonists: two chiral carbons are adjacently structured on the left side of the molecule. To study the relationship between the stereoconfiguration of the vicinal chiral carbons in 1a and beta-AR agonistic activity, the four stereoisomers were synthesized via oxazolidinone prepared by intracyclization involving inversion of the beta-hydroxy group. The in vitro assays using rat atria for beta(1)-AR, rat uteri for beta(2)-AR, and ferret detrusor for beta(3)-AR showed that 1a possessed potent beta(3)-AR agonistic activity (EC(50) = 3.85 nM) and 3700- and 1700-fold selectivity for beta(3)-AR relative to beta(1)- and beta(2)-AR, respectively. Comparison of the four isomers revealed that the (alphaS,betaR)-compound (1a) was not only the most potent agonist but was also the most selective for beta(3)-AR. In the anesthetized rat, intravenous administration of 1a brought about a sufficient decrement of the intrabladder pressure (ED(50) = 12 microg/kg), and intraduodenal administration of 2a, which is the ethyl ester of 1a, led to same result (ED(50) = 0.65 mg/kg). Moreover, no effects on the cardiovascular system were observed in either test.