brl-37344 and Urinary-Incontinence

beta-Adrenoceptors mediate urinary bladder relaxation, and gender, age and hypertension have been linked to bladder dysfunction. Therefore, we have studied whether any of these factors affects the ability of beta-adrenoceptor agonists to relax rat bladder detrusor muscle in vitro. For this purpose we have compared male and female Wistar rats, young and old male Wistar rats, and male normotensive and spontaneously hypertensive rats (SHR). Comparisons were done using KCl-precontracted bladder strips (length about 15-20 mm) and the endogenous agonist noradrenaline, the synthetic non-subtype-selective agonist isoprenaline, and the prototypical beta(3)-adrenoceptor agonists BRL 37,344 and CGP 12,177. While all agonists yielded numerically weaker relaxation in female as compared to male rats (for example for noradrenaline E(max) 40+/-4% vs 53+/-6% relaxation, pEC(50) 5.41+/-0.13 vs 5.60+/-0.14), this difference reached statistical significance only for the weak partial agonist CGP 12,177. Responses to all agonists were attenuated in old as compared to young rats, largely due to a reduced maximum effect, although the difference did not reach statistical significance for isoprenaline. The maximum relaxation responses to noradrenaline and isoprenaline were significantly lower in SHR than in normotensive rats, but both strains exhibited similar responses to the partial agonist BRL 37,344. We conclude that factors associated with bladder dysfunction, such as gender, age and hypertension, can be associated with impaired beta-adrenoceptor-mediated bladder relaxation. However, these alterations are not always consistent across various agonists, and the extent of the differences can be small. Therefore, we propose that beta-adrenoceptor dysfunction may contribute to the pathophysiology of such conditions, but is unlikely to be the only or even the major factor in this regard. We speculate that beta-adrenoceptor agonists may be effective in the treatment of bladder dysfunction under all of these conditions.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Age Factors; Animals; Ethanolamines; Female; Hypertension; In Vitro Techniques; Isoproterenol; Male; Muscle Relaxation; Muscle, Smooth; Norepinephrine; Propanolamines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Adrenergic, beta; Sex Factors; Urinary Bladder; 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.

Topics: Administration, Oral; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Blood Pressure; Colon; Duodenum; Ethanolamines; Heart Rate; In Vitro Techniques; Injections, Intravenous; Male; Muscle Contraction; Norepinephrine; Pressure; Prodrugs; Rats; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3; Stereoisomerism; Structure-Activity Relationship; Tetrahydronaphthalenes; Urinary Bladder; Urinary Incontinence; Urination

With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.

Topics: Adrenergic beta-Agonists; Animals; Blood Pressure; Female; Ferrets; Glycine; Heart Rate; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth; Pregnancy; Pressure; Rats; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Structure-Activity Relationship; Urinary Bladder; Urinary Incontinence; Urination; Uterus