The National Institute of Diabetes & Digestive & Kidney Diseases

The Section on Drug-Receptor Interactions plans and conducts research on the design, synthesis, and biological evaluation of analogues of chemical neurotransmitters, hormones, and other biological regulatory agents and chemical messengers. Ring-fluorinated adrenergic neurotransmitters were shown to have adrenergic receptor selectivity that depended on the site of the fluorine substituent. Development of stereoselective syntheses of fluorinated biogenic amines and amino acids provided new tools for research. New analogues of ascorbic acid were prepared as tools for the study of ascorbic acid biochemistry. Side-chain fluorinated bioimidazoles and bioindoles have been prepared. Fluorinated aryl-cyclopropyl amines are selective and potent inhibitors of monoamine oxidase and semicarbazide-sensitive amine oxidase. Approaches to methylene, fluoromethylene and difluoromethylene analogues of UDP-Glc-NAc are being developed as inhibitors of O-Glc-NAc transferase. New research with 2-fluorohistidine includes biochemical incorporation of this analog into mammalian protein for mechanistic studies.

1. Kirk, KL Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules J. Fluorine Chem.(127): 1013-1029, 2006.

2. Tuan, E, Kirk, KL Fluorine reactivity in difluoromethylimidazoles J. Fluorine Chem.(127): 980-982, 2006.

3. Kirk, KL Selective flourinataion in drug design and development, an overview of biochemical rationales Current Topics Med. Chem.(6): 1447-1456, 2006.

4. Corpe CP, Lee JH, Kwon O, Eck P, Narayanan J, Kirk KL, Levine M 6-Bromo-6-deoxy-L-ascorbic acid: an ascorbate analog specific for Na+-dependent vitamin C transporter but not glucose transporter pathways. J Biol Chem (280): 5211-20, 2005. [Full Text/Abstract]

5. Eichler, JF, Cramer, JC, Kirk, KL, Bann, JG Biosynthesis of Chaperon Protein PapD Incorporating Fluorohistidine ChemBiochem(6): 2170-2173, 2005.

6. Ye S, Yoshida S, Frohlich R, Haufe G, Kirk KL Fluorinated phenylcyclopropylamines. Part 4: Effects of aryl substituents and stereochemistry on the inhibition of monoamine oxidases by 1-aryl-2-fluoro-cyclopropylamines. Bioorg Med Chem (13): 2489-99, 2005. [Full Text/Abstract]

7. Rosen TC, Yoshida S, Kirk KL, Haufe G Fluorinated phenylcyclopropylamines as inhibitors of monoamine oxidases. Chembiochem (5): 1033-43, 2004. [Full Text/Abstract]

8. Yoshida S Meyer OG Rosen TC Haufe G Ye S Sloan MJ Kirk KL Fluorinated phenylcyclopropylamines. 1. Synthesis and effect of fluorine substitution at the cyclopropane ring on inhibition of microbial tyramine oxidase. J Med Chem (47): 1796-806, 2004. [Full Text/Abstract]

9. Rosen TC, Yoshida S, Frohlich R, Kirk KL, Haufe G Fluorinated phenylcyclopropylamines. 2. Effects of aromatic ring substitution and of absolute configuration on inhibition of microbial tyramine oxidase. J Med Chem (47): 5860-71, 2004. [Full Text/Abstract]

10. Yoshida S Rosen TC Meyer OG Sloan MJ Ye S Haufe G Kirk KL Fluorinated phenylcyclopropylamines. Part 3: Inhibition of monoamine oxidase A and B. Bioorg Med Chem (12): 2645-52, 2004. [Full Text/Abstract]

11. Ye S Rezende MM Deng WP Herbert B Daly JW Johnson RA Kirk KL Synthesis of 2'',5''-dideoxy-2-fluoroadenosine and 2'',5''-dideoxy-2,5''-difluoroadenosine: potent P-site inhibitors of adenylyl cyclase. J Med Chem (47): 1207-13, 2004. [Full Text/Abstract]

12. Deng WP Nam G Fan J Kirk KL Syntheses of beta,beta-difluorotryptamines. J Org Chem (68): 2798-802, 2003. [Full Text/Abstract]

13. Borri Voltattorni C Bertoldi M Bianconi S Deng WP Wong K Kim I Herbert B Kirk KL Behavior of fluorinated analogs of L-(3,4-dihydroxyphenyl)alanine and L-threo-(3,4-dihydroxyphenyl)serine as substrates for Dopa decarboxylase. Biochem Biophys Res Commun (295): 107-11, 2002. [Full Text/Abstract]

14. Dolensky B Kirk KL New building blocks for fluorinated bioimidazole derivatives II: preparation of beta-fluorourocanic acids. J Org Chem (67): 3468-73, 2002. [Full Text/Abstract]

15. Dolensky B Kirk KL New building blocks for fluorinated imidazole derivatives: preparation of beta-fluoro- and beta,beta-difluorohistamine. J Org Chem (66): 4687-91, 2001. [Full Text/Abstract]

16. Herbert B Kim IH Kirk KL Synthesis of 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine as potential in vivo precursors of fluorinated norepinephrines. J Org Chem (66): 4892-7, 2001. [Full Text/Abstract]

17. Ge P Kirk KL Synthesis of 2-Deoxy-2-halo-L-ascorbic Acids. J Org Chem (62): 3340-3343, 1997. [Full Text/Abstract]

18. Sloan MJ, Kirk KL Synthesis of a fluorinated analog of 1-aminocyclopropane carboxylic acid. Tetrahedron Letters (38): 1677-1689, 1997.

19. Creveling CR Padgett WL McNeal ET Cohen LA Kirk KL Incorporation of 2-fluorohistidine in murine protein in vivo. Life Sci (51): 1197-204, 1992. [Full Text/Abstract]

20. Eisenhofer G Hovevey-Sion D Kopin IJ Miletich R Kirk KL Finn R Goldstein DS Neuronal uptake and metabolism of 2- and 6-fluorodopamine: false neurotransmitters for positron emission tomographic imaging of sympathetically innervated tissues. J Pharmacol Exp Ther (248): 419-27, 1989. [Full Text/Abstract]