November 6, 2009

Investigators seek alternative to common diuretics

Investigators seek alternative to common diuretics

Jerod Denton, PhD., assistant Professor of Anesthesiology and Pharmacology, and his colleagues are working to develop “potassium-sparing” diuretics that could replace conventional loop diuretics.

Loop diuretics are drugs that inhibit sodium chloride reabsorption in the thick limb of Henle's loop in the nephron, the functional unit of the kidney responsible for generating urine.

In doing so, loop diuretics diminish the osmotic driving force for water reabsorption, leading to the production of a dilute urine, or diuresis. Diuresis, in turn, lowers blood volume and pressure.

While effective, conventional loop diuretics can also lower blood potassium to dangerous levels, leading to irregular heart rhythm and sudden death.

As the elderly population continues to grow and obesity remains a top health issue, the incidence of high blood pressure — and diuretic reliance — continues to rise.

Denton and his colleagues’ efforts are focused on the renal outer medullary potassium channel (ROMK), a membrane protein expressed in the kidney whose function also regulates blood volume and pressure.

“ROMK occupies a unique niche in the nephron in that it regulates both sodium chloride reabsorption and potassium excretion. An intriguing idea in the field is that inhibitory drugs targeting ROMK could lower blood pressure while protecting potassium levels,” said Denton. “If the idea is correct, the development of potassium-sparing diuretics targeting ROMK would be a major advance in anti-hypertensive therapy.”

Currently, however, the true therapeutic value of ROMK is unknown, because there are no drug-like molecules targeting it. Therefore, the Denton lab set out to discover the first small-molecule inhibitors of the channel.

Working in collaboration with scientists in Vanderbilt's High-Throughput Screening Center for GPCRs, Ion Channels, and Transporters, the team performed a screen of approximately 250,000 small molecules for modulators of ROMK function.

Then, Vanderbilt's MLPCN Specialized Chemistry Center got involved, resynthesizing HTS hits and generating drug-like analogs, which afforded several ROMK inhibitors with unprecedented potency and selectivity.

“The collaboration between the Denton Lab, David Weaver's HTS facility and medicinal chemists led to a major advance in the development of selective small molecule inhibitors of ROMK,” said Craig Lindsley, principal investigor of the Vanderbilt Specialized Chemistry Center.

They discovered several inhibitors of ROMK, one of which they published this month in the journal Molecular Pharmacology.

Their work could lay the foundation for “proof-of-concept” experiments in animal models to test whether ROMK is a viable therapeutic target.