James M. CookJames M. Cook

Distinguished Professor

Office: Chemistry 645
Phone: 414-229-5856
e-mail: capncook@uwm.edu
Website: Cook's Group Page

Degree(s):

Ph.D., University of Michigan

Research Description

Professor Cook's group is working in several related fields including Natural Products, Medicinal Chemistry, and Organic Synthesis. More specifically, he is interested in the enantiospecific synthesis of natural products with biological activity and the construction of related heterocycles with enhanced activity. Research of this type has led him into the indole, benzylisoquinoline, and isoquinoline alkaloid areas, as well as the chemistry of the important alkaloids quinine, quinidine and reserpine. His group is also currently involved in the study of ligand-receptor interactions at the molecular level.

Over seventy macroline/sarpagine/ajmaline related alkaloids have been isolated from species of Alstonia. A stereospecific Pictet Spengler reaction developed at Milwaukee has been employed to execute an enantiospecific total synthesis of many of these indole alkaloids (see Figure 1 and Figure 2). Some of these bisindoles exhibit antimalarial activity against Plasmodia falciparum malaria. In addition, the total synthesis (see Figures 3 and 4) of the antileishmanial bisindoles accedinisine and N’-demethylaccedinisine have been completed as well as that of the antihypertensive bisindole, dispegatrine.

 fig01_500
Fig. 1. Indole alkaloids synthesized via the asymmetric Pictet-Spengler reaction via internal asymmetric induction.
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Fig. 2. Indole alkaloids synthesized in regiospecific and enantiospecific fashion from L-valine.
 fig03_500
Fig. 3. Total synthesis of accedinisine precursor
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Fig. 4. Total synthesis of accedinisine and N′-demethylaccedinisine.

The approach is both stereospecific and doubly convergent. The preparation of the antimalarial sarpagine related bisindoles villalstonine and alstonisidine, is also underway.

A general approach for the synthesis of polyquinenes via the Weiss reaction continues in his laboratory. The construction of the [5.5.5.5]fenestrane hexaene (Figure 5) and the related heptaene (Figure 6) are being pursued in regard to the bonding character of molecules formerly proposed to house a planar tetracoordinate carbon atom, a three-center, two electron bond at carbon. Other annulenes such as cyclopentapentalene (Figure 7) are being prepared to examine homoconjugation as well as Hückel pi stability.

 fig05  fig06  fig07
Fig. 5. [5.5.5.5] Fenestrane hexaene. Fig. 6. Heptaene. Fig. 7. Cyclopentapentalene.

The synthesis of beta-carbolines, 2,7-dihydropyridodiindoles, isoquinolines, indolo-pyridoimidazoles and imidazobenzodiazepines, when combined with molecular modeling (see Figure 8), has resulted in the pharmacophores for agonist and inverse agonist activity at benzodiazepine receptors. The inverse agonists are being evaluated for cognitive enhancement, including α5 subtype selective ligands for treatment of Alzheimer’s disease. The agonists at BzR, especially subtype selective α2/α3 agonists, are being evaluated for anxiolytic and anticonvulsant activity, as well as activity against neuropathic pain. Lead compounds in this series are devoid of the muscle relaxant, ataxic, and amnesic effects of Valium. The aim is to provide new drugs with anxiolytic, anticonvulsant and analegsic activity which are devoid of the deleterious side effects of the classical benzodiazepines including abuse potential. This will result in more selective agents to treat a number of CNS disorders.

 fig08_500
Fig. 8. The ligand diazepam docked in the α1γ2 benzodiazepine binding site via a homology model.

In regard to drug development earlier, XHe-II-053, our nonsedating GABA α2/α3 agonist was put in Phase I studies in humans for anxiety disorders. The backup compound HZ 166 is currently being licensed to Addiction Therapeutix, Inc. to treat neuropathic pain. A related α5 subtype selective inverse agonist enhances cognition in both rats and primates and is the target of a joint SBIR grant recently funded with Physiogenix. In regard to treatment of schizophrenia, a GABAergic α5 subtype selective GABA(A) agonist from the anxiety disorders program looks effective in some models of schizophrenia, while a joint SBIR grant and NIDA grant with Promentis/Marquette/UWM targets a different treatment strategy for schizophrenia (these agents were licensed to Promentis). An antialcohol compound was recently licensed to Addiction Therapeutix, Inc. and a number of agents active against drug resistant bacteria, including MRSA, TB and anthrax have been licensed to Macrophyte Inc of Lacrosse (with Dr. Monte and Dr. Schwan).

In a related area of indole chemistry, ligands have been developed that competitively inhibit the enzyme, indoleamine 2,3-dioxygenase. This enzyme is induced to high levels during the immune response and seriously alters the metabolism of tryptophan in inflammatory diseases. This results in increased biosynthesis of kynurenic acid and quinolinic acid followed by cell death. This condition has been implicated in over twenty inflammatory diseases, including acquired immune deficiency syndrome (AIDS), hepatic encephalopathy and polio virus. The inhibitors of this enzyme are designed to reverse the aberrant metabolism of tryptophan in the CNS and return levels of quinolinic acid, etc. to normal.

Selected Publications

"Enantiospecific Total Synthesis of the Important Biogenetic Intermediates Along the Ajmaline Pathway, (+) Polyneuridine and (+) Polyneuridine Aldehyde, as well as 16-Epivellosimine and Macusine A," Yin, W.; Kabir, S. M.; Wang, Z.; Rallapalli, S. K.; Ma, J.; Cook, J. M., J. Org. Chem., 75, 3339-3349 (2010).

"The Asymmetric Pictet-Spengler Reaction," Lorenz, M.; VanLinn, M. L.; Cook, J. M.; Curr. Org. Syn., 7, 189-223 (2010).

"Mechanistic Studies on the Cis to Trans Epimerization of Trisubstituted 1, 2, 3, 4-Tetrahydro-β-carbolines,” Van Linn, M. L.; Cook, J. M., J. Org. Chem., 75, 3587-3599 (2010).

"Anxiolytic-like Effects of 8-Acetylene Imidazobenzodiazepines in a Rhesus Monkey Conflict Procedure,” Fischer, B.; Licata, S.; Edwankar, R.; Wang, Z-J.; Huang, S.; He, X.; Yu, J. Zhou, H.; Johnson, Jr., E. M.; Cook, J. M.; Furtmuller, R.; Ramerstorfer, J.; Sieghart, W.; Roth, B.; Majumder, S.; Rowlett, J., Neuropharmacology, 59, 612-618, (2010).

"Discriminative Stimulus Effects of L-838,417 (7-tert-Butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABA A Receptor Subtypes,” Licata, S. C.; Platt, D. M.; Rüedi-Bettschen, D.; Atack, J. R.; Dawson, G. R.; Van Linn, M. L.; Cook, J. M.; Rowlett, J. K., Neuropharmacology, 58, 357-364 (2010).

"Development of a Two-step Route to 3-PBC and βCCt, Two Agents Active Against Alcohol Self-Administration in Rodent and Primate Models,” Namjoshi, O. A. ; Grzybkowska, A.; Fonseca, G. O.; Van Linn, M.; Wang, Z.; Deschamps. J. R.; Cook, J. M., J. Org. Chem., 76 (11), 4721–4727 (2011).

"HZ-166, A Novel GABAA Receptor Subtype-Selective Benzodiazepine Site Ligand, Is Antihyperalgesic in Mouse Models of Inflammatory and Neuropathic Pain,” Di Lio, A.; Benke, D.;Besson, M.; Desmeules, J.; Daali, Y.; Wang, Z. J.; Edwankar, R.; Cook, J. M.; Zeilhofer, H. U., Neuropharmacology-, 60, 626-632 (2011).

"Regiospecific, Enantiospecific Total Synthesis of C-19 Methyl Substituted Sarpagine Alkaloids Dihydroperaksine-17-al and Dihydroperaksine,” Edwankar, R. V.; Edwankar, C. R.; Deschamps, J.; Cook, J. M., Org Lett., 13, 5216-5219 (2011).

"A Novel α5 GABAAR-Positive Allosteric Modulator Revereses Hyperactivation of the Dopamine System in the MAM Modle of Schizophrenia,” Gill, K.; Lodge, D.; Cook, J. M.; Ara, S.; Grace, A., Neuropsychopharmacology, 36, 1903-1911 (2011).

"Lifelong CRF Overproduction is Associated with Altered Gene Expression and Sensitivity of Discrete GABA (A) and mGlu Receptor Subtypes,” Vinkers, C.; Hendriksen, H.; Oorshot, R.; Cook, J. M.; Rallapalli, S.; Huang, S.; Millian, M.; Oliver, B.; Groenink, L., Psychopharmacology., DOI 10.1007/S 00213-011-2423-0 (2011).

"The Role of α1 and α5 Subunit-Containing GABAA Receptors in Motor Impairment Induced by Benzodiazepines in Rats”, Milic, M.; Divljakovic, J.; Rallapalli, S.; Van Linn, M. L.; Timic, T.; Cook, J. M.; Savic, M. M., Behav. Pharmacol., 23, 191-197 (2012).

"GABAA Receptor α Subunits Differentially Contribute to Diazepam Tolerance After Chronic Treatment,” Vinkers, C.; Hansen, H.; Nielsen, E.; van Oorschot, R.; Cook, J. M.; Groenink, L.; Olivier, B.; Mirza, N., PLOS ONE,, 7 (8) e43054, 1-11 (2012).

"Targeting the Restricted α Subunit Repertoire of Airway Smooth GABA (A) Receptors Augments Airway Smooth Muscle Relaxtion,” Gallos, G.; Yim, P.; Chang, S.; Zhang, Y.; Xu, D.; Cook, J. M.; Gerthoffer, W.; Emala, Sr. C., Am. J. Physiol. Lung Cell Mol. Physiol., 302, 248-256 (2012).

"Base-Mediated Stereospecific Synthesis of Aryloxy and Amino Substituted Ethyl Acrylates”, Kabir*, M.S.; Namjoshi, O. A.; Verma, R.; Lorenz, M.; Tiruveedhula,V.V.N.P.; Monte, A.; Bertz, S. H.; Schwabacher*, A.; Cook*, J. M., J. Org. Chem., 77, 300-310 (2012).

"Brønsted Acid Mediated Cyclization of Enaminones. Rapid and Efficient Access to the Tetracyclic (ABCE) Framework of the Strychnos Alkaloids”, Edwankar, R. V.; Edwankar, C. R.; Namjoshi, O. A.; Deschamps, J. R.; Cook*, J. M., J. Nat. Prod., 75, 181-188 (2012).

"Synthesis and Minimum Inhibitory Concentrations of SK-03-92 against Staphylococcus aureus and other gram-positive bacteria”, Schwan, W. R.; Kabir, M. S.; Kallaus, M.; Krueger, S.; Monte, A.; Cook, J. M., J. Infect. Chemother., 18, 124-126 (2012).

"Benzodiazepine – Induced Spatial Learning Deficits in Rats are Regulated by the Degree of Modulation of α1 GABA (A) Receptors,” Joksimovic, S.; Divljakovic, J.; Van Linn, M.; Varagic, Z.; Brajkovic, G.; Milinkovic, M.; Yin, W.; Timic, T.; Sieghart, W.; Cook, J. M.; Savic, M. M., European J. Neuropsychopharmacology, doi.org/1016/j.eruoneuro.2012.05.003

"Identification of Novel Positive Allosteric Modulators and Null Modulators at the GABA (A) Receptor α+β-Interface”, Varagic, Z.; Ramerstorger, J.; Pantea, M.; Huang, S.; Rallapalli, S.; Sarto-Jackson, I.; Cook, J. M.; Sieghart, W.; Margot, E., British J. Pharmacol., submitted (2012).

"Comparison of Cell Expression Formats for the Characterization of the GABA Channels using Microfluidic Patch Clamp System,” Chen, Q.; Yim, P.; Yuan, N.; Johnson, J.; Cook, J. M.; Smith, S.; Ionescu-Zanetti, C.; Wang, Z.; Arnold, A.; Emala, C., Assay and Drug Development Technologies, 10, 325-335 (2012).

"Effects of the Benzodiazepine GABA α1 Selective Ligand 3-Propoxy-β-Carboline (3PBC) on Alcohol Seeking and Self-Administration in Baboons,” Kaminski, B.; Van Linn, M.; Cook, J.; Yin, Wenyuan; Weerts, E., Psychoparmacology, 00, 0000-0000 (2012).

“Recent Adventures with the Pauson-Khand Reaction in Total Synthesis,” Van Ornum, S.; Hoerner, S.; Cook, J. M., in The Pauson-Khand Reaction: Scope, Variations and Applications, First Edition. Edited by Ramon Rios Torres. John Wiley and Sons, Ltd., Chapter 8, 211-238 (2012).

“Enhancing the Function of Alpha 5-Containing GABA(A) Receptors Promotes Action Potential Firing of Neocortical Neurons During Upstates,” Drexler, B.; Zinser, S.; Huang, S.; Rudolph, U.; Cook, J. M.; Antkowiak, B., 00, 0000-0000 (2012).

"The Ability of Flumazenil to Reverse Diazepam Withdrawal-Induced Anxiety in Rats is Mediated by α1 GABAA Receptors,” Divljakovic, J.; Milic, M.; Namjoshi, O.; Tiruveedhula, P. B.; Cook, J. M.; Savic, M., Brain Res. Bulletin, 00, 0000-0000 (2012).

“Pharmacologic Association Between Binge Drinking and Impulsivity using Triple Monoamine Uptake Inhibitors in High Alcohol-Preferring (HAP) Mice," Tousa, D.; Warnock, K.; Namjoshi, O.; Cook, J. M.; Grahame, N.; June, H., Psychopharmacology, 00, 0000-0000 (2013).

“Coginition Impairing Effects of Benzodiazepine Type Drugs: Evaluation of the Role of GABAA Receptor Subtypes in Spatial Recognition Memory and Executive Function Tasks”, Makaron, L.; Moran, C.; Namjoshi, O.; Rallapalli, S.; Cook, J. M.; Rowlett, J., Eur. J. Neuropsychopharmacology, 00, 0000-0000 (2013).

“Subtype Selectivity of α+β- Site Ligands of GABAA Receptors-Identification of the First Highly Specific Positive Modulators at α6β2/3)2 Receptors”, Varagic, Z.; Ramerstorfer, J.; Huang, S.; Rallapalli, S.; Sarto-Jackson, I.; Cook, J. M.; Sieghart, W.; Margot, E., J. British Pharmacol., 00, 0000-0000 (2013).

“Allosteric Modulation of GABA (A) Receptors Compared to Non-GABAergic Compounds: Effects on Visuo Spatial Memory in Rhesus Monkeys”, Soto, P.; Ator, N.; Rallapalli, S.; Biawat, P.; Clayton, T.; Brayton, C.; Cook, J. M.; Weed, M., Psychopharmacology, 00, 0000-0000 (2013).

Patents

Cook, James M.; Huang, Qi; He, Xiaohui; Li, Xioayan; Yu, Jianming; Han, Dongmei, “Anxiolytic Agents with Reduced Sedative and Ataxic Effects,” US Patent 7,119,196 B2 (2006), 94 pages.

June, Harry L.; Cook, James M.; Ma, Chunrong, "Methods for Reducing Alcohol Cravings in Chronic Alcoholics," U.S. Pat. Appl. Publ. (2003), 60 pp. CODEN: USXXCO US 2003176456 A1 20030918 CAN 139:241570 AN 2003:737374 CAPLUS

Cook, James M.; Zhou, H.; Huang, S.; Sarma, P.V.V.S.; Zhang, C., "Stereospecific Anxiolytic and Anticonvulsant Agents with Reduced Muscle-Relaxant, Sedative-Hypnotic and Ataxic Effects," Provisional patent application 60/584,143 filed June 30, 2004: PCT patent filed June 30, 2005: US patent filed June 30, 2005. Published in 2006. 2006003995 (2006), 89pp. PCT WO2006/004945 A1. Issued 2009 US 7,618,958 (2009).

Cook, James M.; Han, D.; Clayton, T., "GABAergic Agents to Treat Memory Deficits," Provisional patent filed June 30, 2005. Published in 2006. Patent No. PCT/US 2006018721; US Patent No. 7,595,395; issued 7/24/2009.

Cook, James M.; Defoe, L.; Kabir, M. Shahjahan; Monte, A.; Rott, M.; Schwan, W., "US CIP for Anti-infective Agents and Methods of Use," Filed on April 6, 2007 (US Application No. 11/697,582); published 2007, CIP of US ser No. 163,421.

Cook, J. M.; Edwanker, R.; Edwanker, C.; Huang, S.; Jain, H.; Rivas, F.; Yang, J.; Zhou, H., “Selective Anticonvulsant Agents and Their Uses,” Filed provisional patent on 3/20/08.

Cook, J. M.; Clayton, T.; Jain, H.; Teng, Y.; Yang, J.; Rallapalli,S., "GABAergic Receptor Subtype Selective Ligands and Their Uses,” Filed a provisional patent on 5/4/08.

Cook, J. M.; Huang, Q.; He, X.; Li, X.; Yu,J.; Han, D., “Anxiolytic Agents with Reduced Sedative and Ataxic Effects,” Patent Issue No. 2003230754, 2/29/08.

Cook, J. M.; Huang, Q.; He, X.; Li, X.; Yu, J.; Han, D., “Anxiolytic Agents with Reduced Sedative and Ataxic Effects,” Patent Issue No. 255781, 3/31/08.

Cook, J. M.; Huang, Q.; He, X.; Li, X.; Yu, J.; Han, D., “Anxiolytic Agents with Reduced Sedative and Ataxic Effects,” Patent Issue No. 10-0865410, 10/24/08.

Cook, J. M.; Huang, Q.; He, X.; Li, X.; Yu, J.; Han, D., “Anxiolytic Agents with Reduced Sedative and Ataxic Effects,” Divisional Patent Issue No. 547480, 3/13/08.

Cook, J. M.; Van Linn, M.; Yin, W., “Synthesis of Aza Beta Carbolines and Methods of Use,” Provisional patent applied for June 2008. Filed electronically.

Cook, J. M.; Baker, D.; Johnson, E. M.; Yin, W., “Cysteine and Cystine Prodrugs to Treat Schizophrenia and Drug Addiction,” PCT/US 09/047099, filed April 16, 2009; WO 2009/137251A2, International Publication date, Nov. 12, 2009.

Cook, J. M.; Baker, D.; Johnson, E. M.; Yin, W., "Cysteine and Cystine Prodrugs to Treat Schizophrenia and Drug Addiction,” Filed on 8/11/08. Application number 12189516. Published 08/13/2009; PCT WO 2009/100431 A1.

Cook, J. M.; Huang, S.; Edwankar, R.; Namjoshi, O.; Wang, Z., “Selective Agents for Pain Suppression”, US Patent Publication Number US 2010/0317619A1, Pub. Date Dec. 16, 2010.

Cook, J. M.; Rallapalli, S.; Clayton, T.; Jain, H.; Yang, J.; Teng, Y., "Gabaergic Receptor Subtype Selective Ligands and their Uses,” provisional patent filed on 4/28/2011, Application number 6147899.

Cook, J.M.; Baker, D.; Johnson, E. M.; Yin, W., “Cysteine and Cystine Prodrugs to Treat Schizophrenia and Drug Addiction,” US Patent Issued No: US 7,829,709 B1, Nov. 9th 2010.

Cook, James; Van Linn, Michael; Yin, Wenyuan, “Aza-Beta- Carbolines and Method of Using Same,” filed US/22.05.08/USP 55334; Application No/Patent No 09751673.6021/7 PCT/US2009045014.

Cook, J. M.; Monte, A.; Schwan, W.; Kabir, M. S.; Rott, Marc; Miskowski, J., “Broad Spectrum-Gram–Positive–Antimicrobials and Anthemintics with Efficacy Against Drug-Resistant Strains and Mycobacterium Species,” CIP Application filed 12/20/2010, Serial number 12/973, 078 (2010).

Cook, J. M.; Monte, A.; Schwan, W.; Rott, M.; Kabir, M. S., “Broad Spectrum-Gram-Positive-Antimicrobials with Efficacy Against Drug-Resistant Strains and Mycobacterium Species,” Provisional filed, 1/15/2010, Serial number 61/295,384 (2010).

Kabir, M. S.; Cook, J. M.; Monte, A.; Rott, M.; Schwan, W.; Witzigmann, C.; Namjoshi, O.; Tiruveedhula, V.V.N. Phani; Verma, R., "Stereospecific Synthesis of Acrylate Ethers and Amines for Industrial and Medicinal Applications,” Provisional filed 14th March (2012), Serial number 61/610,574.

Cook, J. M.; Baker, D.; Johnson, E. M.; Yin, W., “Cysteine and Cystine Prodrugs to Treat Schizophrenia and Drug Cravings," US Utility Patent, Serial number 12/367,867, Filed 2/9/2009, Issued 5/8/2012.

Cook, J. M.; Baker, D.; Johnson, E. M.; Yin, W., “Cysteine and Cystine Prodrugs to Treat Schizophrenia and Reduce Drug Cravings," US Patent, Divisonal, Serial number 13/465,383; Filed 5/7/2012.

Cook,J. M.; Huang, S.; Edwankar, R.; Namjoshi, O.; Wang, Z., “Selective Agents for Pain Suppression,” US Patent, Published October 27, 2012, Patent number US2010/0261711 A1.

Cook, J. M.; Van Linn, M.; Yin, W., “Aza-Beta Carbolines and Methods of Using Same,” US Patent number: US 8,268,854B2, September 18, 2012.

Cook, J. M.; Baker, D.; Yin, W.; Johnson II, E. M., “Cysteine and Cystine Prodrugs to Treat Schizophrenia and Reduce Drug Cravings,” Publication number US2012/0220596A1, Pub. Date: August 30, 2012.

Stafford, D.; Cook, J. M.; Arnold, A.; Emala, C., “Development of GABA (A) Agonists to Control Airway Hyperresponsiveness and Inflamation in Asthma,” Provisional Patent Filed September 21, 2012, Application number 61703902, confirmation number 2765, RAM number 9468.