PRINCIPAL INVESTIGATORS

Kenner C. Rice, Ph.D., Senior Investigator

Chief, Chemical Biology Research Branch (CBRB)
Chief, Drug Design and Synthesis Section (DDSS)

Post-doctoral Training - Section on Medicinal Chemistry, National Institute on Diabetes and Digestive and Kidney Disease, National Institutes of Health; Advisor: Everette L. May

Ph.D. - Organic Chemistry, Georgia Institute of Technology; Advisor: Dr. John R. Dyer

B.S. - Chemistry, Virginia Military Institute

RESEARCH INTERESTS

Our major research direction is the elucidation of the structure and function of neurotransmitter systems in the mammalian central nervous system (CNS) in normal, drug-altered, and pathological states and the molecular mechanism of action of CNS active drugs. Organic/medicinal chemistry is the foundation of the multidisciplinary approach utilized in these studies that requires the rational design and chemical synthesis of novel agonists, antagonists, imaging agents, affinity ligands, and other drugs for particular applications. Our principal focus is the application of these techniques to study the mechanism of action of abused drugs and the development of medications for the treatment and prevention of drug abuse. Our present research areas are: (1) opioid receptor subtypes, (2) cocaine and other psychomotor stimulants, (3) cannabinoid (marijuana) receptors, (4) the role of corticotropin releasing hormone receptors in the regulation of the hypothalamic-pituitary-adrenal axis coordinating neuroendocrine, autonomic, immune, and behavioral responses to stress, and (5) development of new ligands for PET and SPECT imaging of drug receptors in the CNS of living animals and conscious humans. The multidisciplinary nature of this program requires extensive collaboration with other groups with diverse pharmacological and biological expertise from within and outside of NIH. These studies also require multistep chemical synthesis of gram and larger quantities of target compounds. Our program has provided potential medications, many new research tools, and much valuable technology for drug abuse research. The latter includes the development of the NIH Opiate Total Synthesis that offers synthetic production of both enantiomers of medical opiates and their antagonists and thus independence from foreign sources of opium.

Selected Publications:

1. Xiong, W., Cheng, K., Cui, T., Godlewski, G., Rice, K. C., Xu, Y., Zhang, L. (2011). Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nature Chemical Biology, 7(5), 296-303. See Commentary p. 249-250.

2. Cheng, K., Lee, Y. S., Rothman, R. B., Dersch, C. M., Bittman, R. W., Jacobson, A. E., Rice, K. C. (2011). Probes for narcotic receptor-mediated phenomena. 41. Unusual inverse ?-agonists and potent ?-opioid antagonists by modification of the N-substituent in enantiomeric 5-(3-hydroxyphenyl)morphans. Journal of Medicinal Chemistry, 54(4), 957-969.

3. Jagoda, E. M., Lang, L., McCullough, K., Contoreggi, C., Kim, B. M., Ma, Y., Rice, K. C., Szajek, L., Eckelman, W. C., Kiesewetter, D. (2011). [76Br]BMK-152, a non-peptide analogue, with high affinity and low non-specific binding for the corticotropin-releasing factor type 1 receptor. Synapse, 65(9), 910-918.

4. Kim, J.-H., Deschamps, J. R., Rothman, R. B., Dersch, C. M., Folk, J. E., Cheng, K., Jacobson, A. E., Rice, K. C. (2011). Probes for narcotic receptor-mediated phenomena. 42. Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of rac-(3R,6aS,11aS)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol and -8-ol, The ortho- and para-c oxide-bridged phenylmorphans. Bioorganic and Medicinal Chemistry, 19(11), 3434-3443.

5. Vardanyan, M., Melemedjian, C. K., Price, T. J., Lai, J. Roberts, E., Deschamps, J., Boos, T. L., Jacobson, A. E., Rice, K. C., Porreca, F. (2010). Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist. Pain, 151(2), 257-265.

6. Iyer, M. R., Lee, Y. S., Deschamps, J. R., Rothman, R. B., Dersch, C. M., Jacobson, A. E., Rice, K. C. (2010). Probes for narcotic receptor-mediated phenomena. 40. N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols. Bioorganic and Medicinal Chemistry, 18(1), 91-99.
   

7. Zhang, Y., Lee, Y. S., Rothman, R. B., Dersch, C. M., Deschamps, J. R., Jacobson, A. E., Rice, K. C. (2009). Probes for narcotic-receptor mediated phenomena. 39. Enantiomeric N-substituted benzofuro[2,3-c]pyridin-6-ols: synthesis and topological relationship to oxide-bridged phenylmorphans. Journal of Medicinal Chemistry, Centennial Anniversary Edition, 52(23) 7570-7579.
   

8. Watkins, L. R., Hutchinson, M. R., Rice, K. C., Maier, S. F. (2009). The ‘toll’ of opioid-induced glial activation: Improving the clinical efficacy of opioids by targeting glia. Trends in Pharmacolgical Sciences, 30(11), 581-591.
   

9. Kurimura, M., Liu, H., Sulima, A., Hashimoto, A., Przybyl, A. K., Ohshima, E., Kodato, S., Deschamps, J. R., Dersch, C. M., Rothman, R. B., Jacobson, A. E., Rice, K. C. (2008). Probes for narcotic receptor-mediated phenomena. 37. Synthesis and opioid binding affinity of the final pair of oxide-bridged phenylmorphans, the ortho- and para-b-isomers and their N-phenethyl analogues, and the synthesis of the N-phenethyl analogues of the ortho- and para-d-isomers. Journal of Medicinal Chemistry, 51(24), 7866-7881.
   

10. Zezula, J., Singer, L., Przybyl, A. K., Hashimoto, A., Dersch, C. M., Rothman, R. B., Deschamps, J., Lee, Y. S., Jacobson, A. E., Rice, K. C. (2008). Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans. Organic and Biomolecular Chemistry, 6(16), 2868-2883.