Pharmacology & Toxicology

My research interests are broadly based on the interface of synthetic organic chemistry and medicinal chemistry, and in particular on the drug discovery of bioactive molecules to probe biological systems or act as potential therapeutic agents in neuroscience and oncology. With this general idea in mind, and in active collaboration with other biologists and pharmacologists, my group would like to establish a strong and creative research program that applies state-of-the-art chemical approaches to biological problems impacting diagnosis, prevention and treatment of human diseases.

One of our current efforts is focused on design and synthesis of small molecules for probing function and development of pharmacological tools for understanding the workings of the brain and that of novel therapies for central nervous system (CNS) disorders such as drug abuse and addiction, depression, schizophrenia, pain, and neurodegenerative diseases. The proposed projects in this area include the identification, characterization and optimization of allosteric modulators and inverse agonists of 5-HT2C receptor, and AMPA receptor positive allosteric modulators for preventing neuroapoptosis. Another line of research development centers on the establishment of novel chemical libraries aiming at mechanism-based or lead compound-based cancer drug discovery, particularly by targeting Bcl-2 family proteins and apoptosis pathways, as well as signal transducers and activators of transcription (STATs) with the aid of molecular docking. Specifically, we are developing Bax activators, BH4 domain antagonists of Bcl2, and STAT3 inhibitors as a new class of preventive/therapeutic agents for various human cancers including both ER-positive and ER-negative breast cancer, lung cancer, head/neck cancer, and pancreatic cancer as well as inflammation. Other research efforts include design and synthesis of small molecule probes targeting Epac, which are exchange proteins directly activated by cAMP including cAMP-regulated guanine nucleotide exchange factors. Last but not least, we are also working on natural product-based diversity-oriented synthesis that may lead to exciting potentials for novel small molecule drug discovery.

C. Ding, N. M. Bremer, T. D. Smith, P. K. Seitz, N. C. Anastasio, K. A. Cunningham, J. Zhou. Exploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT2C Receptor Allosteric Modulators. ACS Chem. Neurosci., 2012, 3 (7), 538-545. - Additional Information

J. Feng, G.G. Gurkoff, K.C.Van , M. Song, D.A. Lowe, J. Zhou, B.G. Lyeth. NAAG Peptidase Inhibitor Reduces Cellular Damage in a Model of TBI with Secondary Hypoxia. Brain Res. 2012, 1469, 144-152. - Additional Information

H. Chen, T. Tsalkova, F. C. Mei, Y. Hu, X. Cheng, J. Zhou. 5-Cyano-6-oxo-1,6-dihydro-pyrimidines as Potent Antagonists Targeting Exchange Proteins Directly Activated by cAMP, Bioorg. Med. Chem. Lett., 2012, 22, 4038-4043. - Additional Information

J. Feng, K. C. Vana, G. Gurkoff, C. Kopriva, R. T. Olszewski, M. Song, S. Sun, M. Xu, J. H. Neale, P. Yuen, D. A. Lowe, J. Zhou, B. G. Lyeth, Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI. Brain Res. 2011, 1395, 62-73. - Additional Information

Caldarone B.J., Paterson N.E., Zhou J., Brunner D., Kozikowski A.P., Westphal K., Korte-Bouws G., Prins J., Korte S.M., Olivier B., Ghavami A., The novel triple reuptake inhibitor, JZAD-IV-22, exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties. J. Pharmacol. Exp. Ther. 2010, 335, 762-770. - Additional Information

Zhang B., West E. J., Van K. C., Gurkoff G. G., Zhou J., Zhang X. M., Kozikowski A. P., Lyeth B. G., HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res. 2008, 1226, 181-191. - Additional Information

R. T. Olszewski, M. M. Wegorzewska, A. C. Monteiro, K. Krolikowski, J. Zhou, A. P. Kozikowski, K. Long, J. Mastropaolo, S. Deutsch, J. H. Neale, PCP and MK-801 Induced Positive and Negative Symptoms Reduced by NAAG Peptidase Inhibition via Group II Metabotropic Glutamate Receptors. Biol. Psychiatry, 2008, 63, 86-91. - Additional Information

T. Yamamoto, O. Saito, T. Aoe, A. Bartolozzi, J. Sarva, J. Zhou, A. Kozikowski, B. Wroblewska, T. Bzdega, J. H. Neale, Local administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats. European J. Neurosci., 2007, 25 (1), 147-158. - Additional Information

B. Wang, J. Zhou, M. Lodder, R. D. Anderson, III and S. M. Hecht, Tandemly Activated tRNAs as Participants in Protein Synthesis. J. Biol. Chem., 2006, 281, 13865-13868. - Additional Information

J. Zhou, J. H. Neale, M. G. Pomper, A. P. Kozikowski, NAAG Peptidase Inhibitors and Their Potential for Diagnosis and Therapy. Nature Reviews Drug Discovery, 2005, 4, 1015-1026. - Additional Information

J. Zhou, T. Klass, K. M. Johnson, K. M. Giberson, A. P. Kozikowski, Discovery of Novel Conformationally Constrained Tropane-Based Biaryl and Arylacetylene Ligands as Potent and Selective Norepinephrine Transporter Inhibitors and Potential Antidepressants. Bioorg. Med. Chem. Lett., 2005, 15, 2461-2465. - Additional Information

J. Zhou, Norepinephrine Transporter Inhibitors and Their Therapeutic Potential. Drugs of the Future, 2004, 29 (12), 1235-1244. - Additional Information

J. Zhou, R. He, K. M. Johnson, Y. Ye, A. P. Kozikowski, Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization. J. Med. Chem., 2004, 47 (24), 5821-5824. - Additional Information

J. Zhou, A. Zhang, T. Klass, K. M. Johnson, C. Z. Wang, Y. Ye and A. P. Kozikowski, Biaryl Analogues of Conformationally Constrained Tricyclic Tropanes as Potent and Selective Norepinephrine Reuptake Inhibitors: Synthesis and Evaluation of Their Uptake Inhibition at Monoamine Transporter Sites, J. Med. Chem., 2003, 46, 1997-2007. - Additional Information

R. D. Anderson, III, J. Zhou, S. M. Hecht, Fluorescence Resonance Energy Transfer between Unnatural Amino Acids in a Structurally Modified Dihydrofolate Reductase, J. Am. Chem. Soc., 2002, 124, 9674-9675.  - Additional Information

B. Wang, M. Lodder, J. Zhou, T. T. Baird, Jr., K. C. Brown, C. S. Craik, S. M. Hecht, Chemically Mediated Site-Specific Cleavage of Proteins, J. Am. Chem. Soc., 2000, 122, 7402-7403. - Additional Information