cl-316243 and Urinary-Incontinence

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