Name: John Gerdes
Office: SB 478
After completing a B.S. in Chemistry at Colorado State University (1978), John Gerdes received a Ph.D. in Chemistry from the University of California at Riverside in 1982. Following a postdoctoral position at U. C. Berkeley, he joined Lawrence Berkeley National Laboratory (LBNL) as a staff scientist during 1986. In 1991 he began his industrial experience, working for Zeneca, Ltd., which was followed by a faculty post within the Department of Chemistry at Central Washington University (1995) where he was promoted to Professor in 2001. Subsequently, he joined the Center for Structural and Functional Neuroscience (CSFN) at the University of Montana (2001). He served as the Director of the CSFN Molecular Computational Core Facility (2001-2011). During 2006 he was tenured as a faculty member within the Department of Biomedical and Pharmaceutical Sciences and was advanced to Professor during 2011.
Our research encompasses a full spectrum of medicinal chemistry studies of central nervous system (CNS) transporter proteins, including the serotonin transporter (SERT), norepinephrine transporter (NET), select excitatory amino acid transporters (EAATs), the vesicular glutamate transporter (VGLUT) and the obligate exchange System xc- transporter (XSc-), among others. Additional medicinal investigations include those for NQO1 anti-tumor agents and Arena virus fusion inhibitor ligands.
Portions of our studies focus upon computational modeling, involving superposition-consensus pharmacophore model generation, formation of comparative molecular field analysis (CoMFA) models, and ligand docked protein homology models. Together, the various models serve as key criteria for establishing designs of new ligands and drugs for the CNS target proteins.
Model inspired ligand libraries are routinely synthesized in our lab and then pharmacologically evaluated for target protein binding potency and selectivity. By doing so, we are able to evaluate the predictive qualities of the models, and enhance the ligand pharmacological activities through iterative medicinal chemistry design. The small molecule agents include novel therapeutic drugs, diagnostic probes, and biochemical pharmacological tools.
Select transporter ligands are assessed as diagnostic probes in vivo, by working with our established collaborators. For example, candidate ligands are fashioned as dynamic brain imaging agents for positron emission tomography (PET) studies. CNS PET imaging provides the opportunity to utilize select radiolabeled forms of our ligands (tracers) to gain estimates of the density of the target CNS transporter proteins in living brain and spinal regions of interest. Of current focus are the assessments of key CNS transporter tissue density changes found between healthy wild type versus disease state subjects. For example, one ongoing project includes the evaluation of density changes of the excitatory amino acid transporter 2 (EAAT2) that is localized on astrocytes in the CNS. Our endeavors include the PET imaging of EAAT2 as a means detect transporter density changes associated with amyotrophic lateral sclerosis (ALS) that should provide a means to better understand ALS progression and new emergent therapies within the clinic.
Primate PET imaging determinations of CNS tracer tissue kinetic profiles provide several unique in vivo opportunities. For example, deeper insights of neuropharmacological dynamics associated with modes of actions of CNS therapeutic interventions may be realized. Changes to biological psychiatry circuitry associated with various mental health disorders can be better understood. Additionally, alterations to specific CNS biochemical processes associated with different forms of CNS neurodegenerative diseases may be assessed.
Huang Y, Zheng MQ, Gerdes JM. Development of Effective PET and SPECT Imaging Agents for the Serotonin Transporter: Has a Twenty-Year Journey Reached its Destination? Current Topics in Medicinal Chemistry, 10:1499-1526, 2010
Guo L, Suarez AI, Braden MR, Gerdes JM, Thompson CM. Inhibition of acetylcholinesterase by chormophore-linked fluorophosphonates. Bioorganic Medicinal Chemistry Letters, 20: 1194-1197, 2010.
Patel SA, Rhoderick JF, Burkhart DJ, Nelson JK, Twamley B, Blumenfeld A, Szabon-Watola MI, Trideep Rajale T, Gerdes JM, Bridges RJ, N.R. Natale NR. Isoxazole analogues bind the System Xc- Transporter: Structure-activity Relationship and Pharmacophore Model. Bioorganic Medicinal Chemistry, 18: 202-213, 2010 .
Hassani M, Cai W, Koelsch KH, Holley DC, Rose AS, Olang F, Lineswala JP, Holloway WG, Gerdes JM, Behforouz M, Beall HD. Lavendaycin Antitumor Agents: Structure-based Design, Synthesis, NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Model Validation with Molecular Docking and Biological Studies. Journal of Medicinal Chemistry, 51:3104-3115, 2008.
US Patent 12/077898: Gerdes JM, Bolstad DB, Braden MR, and Barany A.
1-[(2’-substituted)-Piperazin-1’-yl]-isoquinolines as Norepinephrine Transporter Inhibitor Agents as Antidepressants and Positron Emission Tomography Imaging Agents. 2008.
US Patent 11/796,227: Gerdes JM, Bolstad DB, and Kusche BR. Enantiomers of 2’-Fluoroalkyl-6-nitroquipazine as Serotonin Transporter Positron Emission Tomography Imaging Agents and Antidepressant Therapeutics. 2007.
Patel SA, Nagy JO, Gerdes JM, Bolstad ED, Thompson CM. Tetrapeptide Inhibitors of Glutamate Vesicular Transport (VGLUT). Bioorganic and Medicinal Chemistry Letters, 17: 5125-5128, 2007.
Hassani M., Cai W., Holley D.C., Lineswala J.P., Maharjan B.R., Ebrahimian G.R., Seradj H., Stockdale M.G., Mohammadi F., Marivin C.C., Gerdes J.M., Beall H.D., Behforouz M. Novel Lavendaycin Analogues as Antitumor Agents: Synthesis, in vitro Cytotoxicity, Structure-Metabolism and Computational Molecular Modeling Studies with NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Journal of Medicinal Chemistry, 48:7733-7749, 2005.
Esslinger CS, Agarwal S, Gerdes J, Wilson PA, Davis ES, Awes AN, O’Brien E, Mavencamp T, Koch HP. Poulsen DJ, Rhoderick JF, Chamberlin AR, Kavanaugh MP, Bridges R. The Substituted Aspartate Analogue L-b-threo-Benzyl-aspartate Preferentially Inhibits the Neuronal Excitatory Amino Acid Transporter EAAT3. Neuropharmacology, 49:850-861, 2005.
Poss M, Holley DC, Biek R, Cox H, Gerdes J. Development of a Homology Model for Clade A Human Immunodeficiency virus type 1 gp120 to Localize Temporal Substitutions Arising in Recently Infected Women. Journal of General Virology, 85:1479-1484, 2004.
O’Neil JP, VanBrocklin HF, Bolstad DB, Gerdes JM, Kusche BR. Serotonin Transporter Ligands: Synthesis of (±)-[11C]2’-Methoxymethyl-6-nitroquipazine. Journal of Labelled Compounds and Radiopharmaceuticals, 46:S171, 2003. (scroll to page S171 to view).
Gerdes J.M., DeFina S.C., Wilson P.A., Taylor S.E.. Serotonin Transporter Inhibitors: Syntheses And Binding Potency of (rac)-2'- and (rac)-3'-Methyl-6-nitroquipazine. Bioorganic and Medicinal Chemistry Letter, 10:2643-46, 2000.