Dr. Kenneth A. Jacobson, chief of NIDDK's molecular recognition section and director of the new Chemical Biology Core Facility, was recently awarded the Hillebrand Prize. Given annually by the Chemical Society of Washington, the prize honors scientists who have made original contributions to the science of chemistry.

During his 21 years at NIH, Jacobson, a medicinal chemist, has focused on the structure and pharmacology of cell surface receptors. With a wide range of physiological and disease-related effects, receptors have generated considerable interest in recent years as potential targets for drug therapies. Jacobson has studied how adenosine and nucleotide receptors interact with their ligands, the small molecules that bind to the receptors, with the goal of exploring possible clinical applications.

Dr. Kenneth A. Jacobson, chief of NIDDK's molecular recognition section and director of the new Chemical Biology Core Facility, was recently awarded the Hillebrand Prize.

To understand the physiology of the receptors and their interactions with various ligands, it is necessary to selectively activate or block the receptors' response using small molecules. Agonists are ligands that stimulate a receptor response; antagonists block a response. Jacobson's group developed a number of computer models to allow investigators to examine how agonists and antagonists recognize their specific receptor targets and interact with them.

Building on this work, Jacobson and his group also have designed and synthesized a number of potent and highly selective agonists and antagonists for three types of adenosine receptors (the A₁, A_2B, and A₃ types) and for P2Y₁ nucleotide receptors. These agonists and antagonists are widely used as pharmacologic research tools, and Jacobson's novel chemical probes have been used by researchers in studies described in hundreds of scientific papers. In fact, he has been recognized as one of the most highly cited pharmacologists in the world.

Two factors make these molecules particularly useful. One is their specificity — the ligands target particular receptors, which allows investigators to conduct their work with much greater confidence and precision. The other is that many of Jacobson's adenosine antagonists appear to be useful across animal species, so that scientists working with mouse, bovine or other animal cells can all benefit from using these molecules. "Dr. Jacobson and his colleagues have provided a pharmacologic foundation that has helped an entire field of science move forward in major ways," said T. Kendall Harden, professor of pharmacology at the University of North Carolina School of Medicine and Jacobson's current collaborator on nucleotide receptors research.

The clinical applications of this field of basic science already have been realized in several areas, including asthma, cystic fibrosis, thrombosis, stroke, neurodegenerative diseases, cardiovascular disease and glaucoma. For example, in collaborative studies with the University of Pennsylvania Medical Center, Jacobson and Dr. Bruce Liang built on longstanding knowledge that adenosine protects the heart when it is overstressed. This molecule binds to receptors on cell surfaces, rendering the cells more resistant to the harmful effects of coronary artery blockages. Using chick cells, Jacobson and Liang found that agonists that activated the A₃ receptor type caused sustained protection, whereas agonists that activated the A₁ type had only a short-term effect. They found, however, that activation of both A₁ and A₃ receptors provided added protection. They also found that co-activating adenosine receptors can "pre-condition" heart cells and shield them from subsequent damage. These findings may lead to the development of drugs that may someday help to prevent ischemia and heart attacks as well as lessen the chances of post-surgical heart attacks.

A₃ antagonists developed by Jacobson's group have also been invaluable in glaucoma research. When A₃ receptors in cells of the ciliary epithelium stimulate the release of salts and accompanying fluid into the eye, intraocular pressure, which can lead to glaucoma, increases. Researchers hypothesized that blocking A₃ receptors in the ciliary epithelium would reduce the rate of fluid formation in the eye, thereby reducing intraocular pressure and the risk of this debilitating eye disease. Studies in wild-type and knock-out mice have shown that A₃ antagonists in fact lower intraocular pressures, suggesting a potentially innovative approach to treating glaucoma in the future. "The development of these molecules has greatly facilitated research and generated many ideas about ways to address important health problems," said Dr. Mortimer Civan, a glaucoma researcher at the University of Pennsylvania.

Jacobson has authored or coauthored 400 original research papers, edited three books and is listed as inventor on 40 patents. He has trained dozens of postdoctoral fellows, and served on the editorial advisory boards of several major scientific journals. In 1996, he received the first Fassina Award for contributing important and novel chemical probes to purinergic research. In 2001, he was awarded the Roon Lectureship at Scripps Research Institute, LaJolla, Calif. Jacobson is also currently the national chair of the American Chemical Society's medicinal chemistry division, serving 10,000 members worldwide.