Researchers at the Georgia Institute of Technology, in collaboration with colleagues at Mercer University, have developed what are believed to be the first orally active selenium-based antihypertensive compounds.
Beyond their potential value in treating high blood pressure, the phenylaminoalkyl selenide compounds could also point the way toward other selenium-based therapeutic agents -- and help expand knowledge of the role this trace element plays in human health.
Development and testing of the patented compounds, which have been studied so far only in animals, are reported in the November issue of The Journal of Pharmacology and Experimental Therapeutics.
"We think our antihypertensive compounds are the first in which biological activity is a consequence of the unique chemistry and biochemistry of selenium," explained Dr. Sheldon W. May, Regents' Professor in Georgia Tech's School of Chemistry and Biochemistry. "We look at this as a paradigm for understanding selenium's chemistry and biochemistry and using that knowledge to incorporate selenium into rationally designed molecules that could have therapeutic potential for many different applications."
Researchers Use Rational Drug Design Techniques
Using rational design techniques, the research team developed a series of derivatives based on their original selenium-based antihypertensive compound. The derivatives were designed to minimize absorption into the central nervous system and to resist damage from enzymes in the gastrointestinal tract.
The biochemistry and pharmacology of selenium are subjects of intense current interest because of evidence that a deficiency of the trace nutrient may play a role in diseases as diverse as cancer, heart disease, arthritis and AIDS. Selenium is an antioxidant involved in many important enzyme processes.
Georgia Tech researchers developed the family of selenium compounds and recognized their antihypertensive potential in the mid-1980s. But concerns about the potential toxicity of selenium and the availability of other blood pressure medications halted further development until recent reports highlighting selenium's potential importance prompted renewed interest.
"There are many kinds of antihypertensives on the market that act in different ways," May said. "We don't believe these compounds have a unique mechanism of action. What is exciting is that their biochemical activity depends on selenium."
Researchers From Mercer University Collaborate on Studies
To develop a better understanding of the compounds' potential value, May's research group collaborated with Dr. Stanley H. Pollock, a professor in the School of Pharmacy at Mercer University. Pollock's collaboration facilitated testing in a strain of rats that spontaneously develops high blood pressure, confirming the compounds' antihypertensive effects.
"We now have clear evidence that these molecules act on the peripheral nervous system and allow the blood vessels to relax sufficiently so that blood flow increases," May said. Behavioral studies of the rats also showed that a hydroxylated derivative of the compound has minimal effect on the central nervous systems of the test animals."
Analytical Techniques Confirm Animal Studies
Using Doppler-based blood flow measurement techniques pioneered by Dr. Ajit Yoganathan at Georgia Tech, the researchers also confirmed that the selenium-based compounds decrease blood pressure and increase blood velocity without increasing heart rate in the experimental animals.
Finally, inductively coupled plasma/mass spectroscopy analytical techniques conducted in collaboration with Dr. Richard Browner at Georgia Tech allowed the researchers to study levels of selenium in various body tissues of the animals to gain an understanding of how it is metabolized. Levels of the hydroxylated selenium compound in brain tissue were significantly lower than in other tissues, confirming the findings of the behavioral studies.
The compounds are therapeutically active at concentrations several orders of magnitude less than the toxic dose. No detrimental side effects were observed in the animal testing, but much more preclinical work would be necessary before application could be made to test the new molecules in humans, he noted.
Additional Study May Show Health Role of Selenium
May believes the work so far has shown the potential of selenium-based compounds as therapeutic agents. He would like to partner with a pharmaceutical company to continue the development, and use analytical techniques developed for studying this compound to explore other aspects of selenium biochemistry.
"We'd like to explore other possible applications of selenium biochemistry and how new therapeutic entities might be developed for other diseases, based on what we know and are learning about these compounds," he said. "The real value of these antihypertensive compounds may be to show how we might make selenium-containing therapeutic agents for other diseases."
Recent studies suggest a selenium deficiency can play a role in determining the survival rate of persons infected with the HIV virus, the rate of certain cancers, and cardiovascular health. A landmark study reported in the December 25, 1996 issue of the Journal of the American Medical Association reported the potential of selenium in reducing cancer rates. Another study, reported in the journal Nature Medicine, showed that a normally benign virus can mutate and cause heart damage in experimental animals that have a selenium deficiency.
Four patents have been issued for the compounds.
Georgia Tech's research on selenium-based antihypertensives was sponsored by the U.S. National Institutes of Health. In addition to those already named, the research team included Languing Wang, Michelle M. Gill-Woznichak, Alison A. Ogonowski, Jennifer Overcast, Ann Ensley, Dr. Shengqiu He and Dr. James B. Smith.
Journal
Journal of Pharmacology and Experimental Therapeutics