Relationship between stereochemistry and the beta3-adrenoceptor agonistic activity of 4'-hydroxynorephedrine derivative as an agent for treatment of frequent urination and urinary incontinence.

Article Details

Citation

Copy to clipboard

Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Ishikawa T, Kobayashi J, Akahane S, Akahane M

Relationship between stereochemistry and the beta3-adrenoceptor agonistic activity of 4'-hydroxynorephedrine derivative as an agent for treatment of frequent urination and urinary incontinence.

J Med Chem. 2003 Jan 2;46(1):105-12.

PubMed ID

12502364 [ View in PubMed

]

Abstract

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)ethy l)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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Isoprenaline	Beta-3 adrenergic receptor	EC 50 (nM)	87	N/A	N/A	Details