Ferreting out a treatment

Urinary incontinence is common in many disease states and is found among women after childbirth and in the elderly. Voluntary control of either the detrusor, the muscle of the bladder wall, or the urethral sphincter is lost, leading to the often embarrassing and unpleasant condition. Increased urination frequency is a common side effect of prostate problems and certain antihypertensives.

The National Kidney and Urologic Diseases Advisory Board (Bethesda, MD) estimates that 13 million people in the United States suffer from urinary incontinence, resulting in an annual direct cost of several billion dollars. Although many centers are investigating medical solutions to bladder dysfunction, muscle instability, reduced bladder-sphincter coordination, and absent and exaggerated reflexes, current drugs have little effect or undesirable side effects.

Recently, however, Nobuyuki Tanaka and colleagues at Kissei Pharmaceuticals in Nagano (Japan) developed a novel assay based on an isolated ferret detrusor to estimate agonistic activity of several ritodrine derivatives (J. Med. Chem. 2001, 44, 1436–1445).

Urine storage is controlled by β3-adrenoceptors that receive signals from sympathetic nerves in the detrusor. Tanaka’s team reasoned that agonists might provide a new approach for the treatment of bladder malfunction. Antimuscarinic drugs are prescribed for urinary incontinence but are contraindicated in patients with urinary retention. β3-Agonists, however, do not exhibit such side effects but perturb the β1- and β2-adrenoceptors involved in cardiovascular and respiratory functions. With this in mind, the team set out to find β3-agonists that might surmount these problems.

Substitution of halogens into the ritodrine phenyl ring increased potency and selectivity for the β3-adrenoceptor, while the position of substitution (ortho or meta) determined by what factor. Four chlorine-substituted derivatives exhibited the greatest β3-adrenoceptor-mediated relaxation of the ferret detrusor and were selective over the β1- and β2-receptors. Studies in anesthetized male rats demonstrated that one of these four compounds significantly reduced urinary bladder pressure.The lack of β1 and β2 activity should result in fewer cardiovascular side effects, such as tachycardia and tremor.