Kenneth A. Jacobson, Ph.D. : NIDDK

Kenneth A. Jacobson, Ph.D.

Chief, Molecular Recognition Section
Acting Chief, Laboratory of Bioorganic Chemistry

NIDDK, National Institutes of Health
Building 8A, Room B1A19
8 Center Dr.
Bethesda, MD 20892-0810
Tel: 301-496-9024
Fax: 301-480-8422

Research Website:

Education / Previous Training and Experience:
B.A., Reed College, 1976
M.S., University of California, San Diego, 1978
Ph.D., University of California, San Diego, 1981

Research Statement:

Dr. Jacobson is a medicinal chemist with interests in the structure and pharmacology of receptors and in developing drugs that act as agonists or antagonists of G protein-coupled receptors (GPCRs). The current focus is on receptors for purines, encompassing both adenosine receptors and P2 receptors, which are activated by ATP and UTP. Dr. Jacobson has taken an interdisciplinary approach to studying the chemical and biological aspects of these receptors. He has developed a "functionalized congener approach" to drug design. Novel ligands (small molecules) for these receptors are developed using classical synthetic approaches and also by semi-rational methods based on molecular modeling and template design. Receptors are computer-modeled by homology to rhodopsin, and the models for ligand recognition are tested and refined using site-directed mutagenesis of the receptor proteins. Recently, the involvement of extracellular loops of GPCRs have been implicated in the receptor binding of small molecules, as demonstrated through the mutagenesis and modeling of P2Y1 receptors.

Substances developed as potent and selective agents acting through adenosine and P2 receptors have proven useful as pharmacological probes and have potential for treating diseases of the central nervous system, immune system, and cardiovascular system. Recent accomplishments include the design and synthesis of the first A3 adenosine receptor agonists and antagonists, using a combination of library screening and optimization of known adenosine receptor ligands. These substances have been shown to be effective in models of treatment of glaucoma, cancer, stroke, and cardiac ischemia. A selective A3 adenosine receptor agonist developed in our laboratory is currently in clinical trials for colon carcinoma and rheumatoid arthritis. We have synthesized the first P2Y1 receptor-selective antagonists, through functionalization of adenine nucleotides. The antagonists were optimized with the aid of receptor homology modeling. These substances have been shown to be effective in models of antithrombotic treatment, due to blockade of the proaggregatory effects of ADP. The pharmacological probes designed in our section have been used to demonstrate the connection between purine receptors and apoptosis (programmed cell death). A3 adenosine receptor agonists at low concentrations and P2Y6 receptor agonists have antiapoptotic effects.

Another potential means of using the protective effects of AR activation was achieved through receptor engineering. Constitutively active mutant A3 adenosine receptors, in principle, could be delivered by tissue-targeted vectors for gene therapy. In addition, we have introduced the approach of “neoceptors”, also intended for eventual use in gene therapy, in which the putative agonist binding site is redesigned to accept only agonist molecules altered in a complementary fashion. Insight into the recognition of agonist by the receptors may be gained using site-directed mutagenesis and molecular modeling. We are exploring this approach conceptually with tailor-made agonist ligands (“neoligands” that are selective for the neoceptor and not the native receptor) in combination with receptor mutagenesis. The neoceptor concept has so far been applied to A2A and A3 adenosine receptors.

Selected Publications:

1. Gao ZG, Jacobson KA Emerging adenosine receptor agonists. Expert Opin Emerg Drugs(12): 479-92, 2007. [Full Text/Abstract]

2. Jacobson KA, Gao ZG, Liang BT Neoceptors: reengineering GPCRs to recognize tailored ligands. Trends Pharmacol Sci(28): 111-6, 2007. [Full Text/Abstract]

3. Ko H, Fricks I, Ivanov AA, Harden TK, Jacobson KA Structure-activity relationship of uridine 5''-diphosphoglucose analogues as agonists of the human P2Y14 receptor. J Med Chem(50): 2030-9, 2007. [Full Text/Abstract]

4. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature(446): 1091-5, 2007. [Full Text/Abstract]

5. Jacobson KA, Gao ZG  Adenosine receptors as therapeutic targets.  Nat Rev Drug Discov (5): 247-64, 2006. [Full Text/Abstract]

6. Jacobson KA, Ohno M, Duong HT, Kim SK, Tchilibon S, C esnek M, Holy A, Gao ZG  A Neoceptor Approach to Unraveling Microscopic Interactions between the Human A(2A) Adenosine Receptor and Its Agonists.  Chem Biol (12): 237-247, 2005. [Full Text/Abstract]

7. Joshi BV, Moon HR, Fettinger JC, Marquez VE, Jacobson KA  A New Synthetic Route to (North)-Methanocarba Nucleosides Designed as A(3) Adenosine Receptor Agonists.  J Org Chem (70): 439-447, 2005. [Full Text/Abstract]

8. Gao ZG, Kim SK, Ijzerman AP, Jacobson KA  Allosteric modulation of the adenosine family of receptors.  Mini Rev Med Chem (5): 545-53, 2005. [Full Text/Abstract]

9. Kim HS Ohno M Xu B Kim HO Choi Y Ji XD Maddileti S Marquez VE Harden TK Jacobson KA  2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonists.  J Med Chem (46): 4974-87, 2003. [Full Text/Abstract]

10. Jacobson KA Jarvis MF Williams M  Purine and pyrimidine (P2) receptors as drug targets.  J Med Chem (45): 4057-93, 2002. [Full Text/Abstract]

Page last updated: January 06, 2009

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