Relationship between stereochemistry and the beta3-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.
Tanaka
Nobuyuki
N
Central Research Laboratory, Kissei Pharmaceutical Company Ltd., 4365-1, Hotaka, Nagano, 399-8304, Japan. nobuyuki_tanaka@pharm.kissei.co.jp
Tamai
Tetsuro
T
Mukaiyama
Harunobu
H
Hirabayashi
Akihito
A
Muranaka
Hideyuki
H
Ishikawa
Takehiro
T
Kobayashi
Junichi
J
Akahane
Satoshi
S
Akahane
Masuo
M
D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000502:physiology; D004386:Duodenum; D004983:Ethanolamines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011312:Pressure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D001743:Urinary Bladder / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy*; D014554:Urination / Q000187:drug effects*
C470652:2-(2-chloro-4-(2-((2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)phenoxy)acetic acid; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D011355:Prodrugs; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; C114929:SR 59104A; D013764:Tetrahydronaphthalenes; C470653:ethyl 2-(2-chloro-4-(2-((2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)phenoxy)acetate; D009638:Norepinephrine