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Craig W. Lindsley

Title and Contact Information

Professor of Pharmacology & Chemistry
Office: 12415-D MRBIV
Phone: (615) 322-8700
EmailWebsite

Education

Ph.D., UCSB

Specialties

VICB
Organometallic Chemistry
Organic Chemistry
Natural Products
Medicinal Chemistry
Chemical Biology
Bioorganic Chemistry
Asymmetric Catalysis

In the News

VICC-VU Joins Effort To Develop New Cancer
VICC-Vanderbilt Investigators Identify Potential New Cancer Drug Compounds
VICC-Zebrafish Swim Into Drug Development
Reporter-Lindsley named editor of neuroscience journal
Research News @ Vanderbilt-Fragile X most common genetic cause of autism
Reporter-VU, Janssen team in drug discovery effort
Reporter-Center for Neuroscience Drug Discovery expanding
Reporter-Craig Lindsley and colleagues have a collaboration with Bristol-Myers to discover Parkinson's therapies
Reporter-Craig Lindsley, Terry Lybrand, and colleagues reveals VU ties that bind
Reporter-Lindsley honored for impact on medicinal chemistry field
Research News @ Vanderbilt-New approach may halt glioblastoma's ability to grow
Research News @ Vanderbilt-ASPET honors Lindsley's pharmacology research
Research News @ Vanderbilt-Small molecule protects kidney filter
Research News @ Vanderbilt-Enzyme holds the door for influenza

Lindsley

Research

The Lindsley research group at Vanderbilt University is a unique environment for graduate and postgraduate training. The primary focus of research in our group is synthetic chemistry (total synthesis and synthetic methodology), drug discovery, and medicinal chemistry. The Lab features state-of-the-art technology, typically found only in major pharmaceutical companies, and a diverse group of scientists: staff synthetic and medicinal chemists, experienced Ph.D. Medicinal Chemists from Big Pharma, staff chromatography specialists and a diverse pool of graduate students pursuing Ph.D.s in Chemistry, Pharmacology and Chemical & Physical Biology.

A major focus of our group is synthetic organic chemistry. Graduate students in chemistry will have the opportunity to pursue the total synthesis of a complex, pharmacologically relevant natural product in order to develop classical synthetic skills. Another area of interest is methodology development in the fields of organocatalysis in order to facilitate library synthesis of key intermediates that can be elaborated towards pharmaceutical targets. Our lab has developed methods to generate enantio-enriched beta-fluoroamines, which can be used to improve pharmokinetic properties of drugable compounds, in addition to completing five total syntheses since October 2006 (carpanone, dispyrin, ciliatimides A-C, 8-epi-lucentamycin A, brevisamide) with many more nearing completion.

All members of our lab will collaborate with other members of the Pharmacology, Drug Metabolism, and Clinical Pharmacology departments to pursue small molecule hits from high throughput screens, perform lead optimization studies to develop structure-activity-relationships (SAR) and ultimately deliver small molecules with acceptable properties to validate novel targets/mechanisms in vivo animal models of target diseases. The molecular targets of interest are kinases, GPCRs, ion channels, nuclear hormone receptors and protein-protein interactions, with an emphasis on allosteric modulation as opposed to classical agonism/antagonism. Therapeutic areas of interest span cancer, neuroscience (schizophrenia, anxiety, pain, sleep, Parkinson's disease) and endocrinology (diabetes, obesity). Students will be exposed to every phase of classical drug discovery. As Director of Medicinal Chemistry in the Vanderbilt Program in Drug Discovery and Director of the Vanderbillt Specialized Chemistry Center (MLPCN), training in my laboratory will be broad and involve organic synthesis, medicinal chemistry, pharmacology and drug metabolism. For many programs in the neuroscience area, students will have the opportunity to also develop radioligands for binding assay development and PET tracers for imaging studies.

Another focus in the Lindsley group is parallel synthesis and the development of new technologies for library synthesis. The lab has state-of-the-art microwave synthesis technology, a mass-directed HPLC purification platform, automated normal and reverse phase chromatography, analytical and preparative chiral HPLC and a large collection of monomers and polymer-supported reagents. There are a number of projects directed at synthesizing libraries of small molecule protein-protein inhibitors, target family-directed libraries and other drug-like small molecule libraries for use in high throughput screening efforts.

Selected Publications

Scott, S. A., Mathews, T. P., Ivanova, P. T., Lindsley, C. W., Brown, H. A. Chemical modulation of glycerolipid signaling and metabolic pathways. Biochimica et Biophysica Acta. 2014, 0 (0): [Epub ahead of print].

Byun, N. E., Grannan, M., Bubser, M., Barry, R. L., Thompson, A., Rosanelli, J., Gowrishankar, R., Kelm, N. D., Damon, S., Bridges, T. M., Melancon, B. J., Tarr, J. C., Brogan, J. T., Avison, M. J., Deutch, A. Y., Wess. J., Wood, M. R., Lindsley, C. W., Gore, J. C., Conn, P. J., Jones, C. K. Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100. Neuropsychopharmacology. 2014, 0 (0): [Epub ahead of print].

Sheffler, D. J., Nedelovych, M. T., Williams, R., Turner, S. C., Duerk, B. B., Robbins, M. R., Jadhav, S. B., Niswender, C. M., Jones, C. K., Conn, P. J., Daniels, R. N., Lindsley, C. W. Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: development of a [3.3.0]-based series and other piperidine bioisosteres. Bioorganic & Medicinal Chemistry Letters. 2014, 24 (4): 1062-6.

Morris, L. C., Days, E. L., Turney, M., Mi, D., Lindsley, C. W., Weaver, C. D., Niswender, K. D. A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors. Journal of Biomolecular Screening. 2014, 0 (0): [Epub ahead of print].

Gregory, K. J., Nguyen, E. D., Malosh, C., Mendenhall, J. L., Zic JZ, Bates B. S., Noetzel, M. J., Squire, E. F., Turner, E. M., Rook, J. M., Emmitte, K. A., Stauffer, S. R., Lindsley, C. W., Meiler, J., Conn, P. J. Identification of Specific Ligand-Receptor Interactions That Govern Binding and Cooperativity of Diverse Modulators to a Common Metabotropic Glutamate Receptor 5 Allosteric Site. ACS Chemical Neuroscience. 2014, 0 (0): [Epub ahead of print].

Foster, D. J., Gentry, P. R., Lizardi-Ortiz, J. E., Bridges, T. M., Wood, M. R., Niswender, C. M., Sulzer, D., Lindsley, C. W., Xiang, Z., Conn, P. J. M5 Receptor Activation Produces Opposing Physiological Outcomes in Dopamine Neurons Depending on the Receptor's Location. The Journal of Neuroscience. 2014, 34 (9): 3253-62.

Gregory, K. J., Nguyen, E. D., Reiff, S. D., Squire, E. F., Stauffer, S. R., Lindsley, C. W., Meiler, J., Conn, P. J. Probing the Metabotropic Glutamate Receptor 5 (mGlu(5)) Positive Allosteric Modulator (PAM) Binding Pocket: Discovery of Point Mutations That Engender a "Molecular Switch" in PAM Pharmacology. Molecular Pharmacology. 2013, 83 (5): 991-1006.

Noetzel, M. J., Gregory, K. J., Vinson, P. N., Manka, J. T., Stauffer, S. R., Lindsley, C. W., Niswender, C. M., Xiang, Z., Conn, P. J. A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling. Molecular Pharmacology. 2013, 83 (4): 835-847.

O'Reilly, M. C., Matthew C., Scott, S. A., Brown, K. A., Oguin, T. H., Thomas, P. G., Daniels, J. S., Morrison, R., Brown, H. A., Lindsley, C. W. Development of Dual PLD1/2 and PLD2 Selective Inhibitors from a Common 1,3,8-Triazaspiro[4.5]decane Core: Discovery of ML298 and ML299 That Decrease Invasive Migration in U87-MG Glioblastoma Cells. Journal of Medicinal of Chemistry. 2013, 56 (6): 2695-2699.

Mueller, R., Dawson, E. S., Meiler, J., Rodriguez, A. L., Chauder, B. A., Bates, B. S., Felts, A. S., Lamb, J. P., Menon, U. N., Jadhav, S. B., Kane, A. S., Jones, C. K., Gregory, K. J., Niswender, C. M., Conn, P. J., Olsen, C. M., Winder, D. G., Emmitte, K. A., Lindsley, C. W. Discovery of 2-(2-Benzoxazoyl amino)-4-Aryl-5-Cyanopyrimidine as Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptor 5 (mGlu5): From an Artificial Neural Network Virtual Screen to an In Vivo Tool Compound. Chemmedchem. 2012, 7 (3): 406-414.

Thomsen, M., Lindsley, C. W., Conn, P. J., Wessell, J. E., Fulton, B. S., Wess, J., Caine, S. B. Contribution of both M-1 and M-4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice. Psychopharmacology. 2012, 220 (4): 673-685.

Lindsley, C. W., Fadeyi, O. O., Senter, T. J., Hahn, K. N. A Versatile Enantioselective Synthesis of Azabicyclic Ring Systems: A Concise Total Synthesis of (+)-Grandisine D and Unnatural Analogues. Chemistry-A European Journal. 2012, 18 (19): 5826-5831.

Lindsley, C. W., Hopkins, C. R. Metabotropic glutamate receptor 4 (mGlu(4))-positive allosteric modulators for the treatment of Parkinson's disease: historical perspective and review of the patent literature. Expert Opinion on Therapeutic Patents. 2012, 22 (5): 461-481.

Noetzel, M. J., Rook, J. M., Vinson, P. N., Cho, H. P., Days, E., Zhou, Y., Rodriguez, A. L., Lavreysen, H., Stauffer, S. R., Niswender, C. M., Xiang, Z. X., Daniels, J. S., Jones, C. K., Lindsley, C. W., Weaver, C. D., Conn, PJ. Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5in Regulating Central Nervous System Function. Molecular Pharmacology. 2012, 81 (2): 120-133.

Wells, C. A., Betke, K. M., Lindsley, C. W., Hamm, H. E. Label-Free Detection of G Protein-SNARE Interactions and Screening for Small Molecule Modulators. ACS Chemical Neuroscience. 2012, 3 (1): 69-78.

Melancon, B. J., Hopkins, C. R., Wood, M. R., Emmitte, K. A., Niswender, C. M., Christopoulos, A., Conn, P. J., Lindsley, C. W. Allosteric Modulation of Seven Transmembrane Spanning Receptors: Theory, Practice, and Opportunities for Central Nervous System Drug Discovery. Journal of Medicinal Chemistry. 2012, 55 (4): 1445-1464.

Xiang, Z. X., Thompson, A. D., Jones, C. K., Lindsley, C. W., Conn, P. J. Roles of the M1 Muscarinic Acetylcholine Receptor Subtype in the Regulation of Basal Ganglia Function and Implications for the Treatment of Parkinson's Disease. Journal of Pharmacology and Experimental Therapeutics. 2012, 340 (3): 595-603.

Lindsley, C. W., Brown, H. A. Phospholipase D as a Therapeutic Target in Brain Disorders.  Neuropsychopharmacology. 2012, 37 (1): 301-302.

Selvy, P. E., Lavieri, R. R., Lindsley, C. W., Brown, H. A., Niswender, C. M. Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu(4)) antagonist: Unexpected 'molecular switch' from a closely related mGlu(4) positive allosteric modulator. Bioorganic & Medicinal Chemistry Letters. 2011, 21 (23): 6955-6959.

Lindsley, C. W., Bates, B. S., Menon, U. N., Jadhav, S. B., Kane, A. S., Jones, C. K., Rodriguez, A. L., Conn, P. J., Olsen, C. M., Winder, D. G., Emmitte, K. A. (3-Cyano-5-fluorophenyl)biaryl Negative Allosteric Modulators of mGlu(5): Discovery of a New Tool Compound with Activity in the OSS Mouse Model of Addiction. ACS Chemical Neuroscience. 2011, 2 (8): 471-482.

Robichaud, A., Engers, D. W., Lindsley, C. W., Hopkins, C. R. Recent Progress on the Identification of Metabotropic Glutamate 4 Receptor Ligands and Their Potential Utility as CNS Therapeutics. ACS Chemical Neuroscience. 2011, 2 (8): 433-449.

Mattmann, M. E., Stoops, S. L., Lindsley, C. W. Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape. Expert Opinion on Therapeutic Patents. 2011, 21 (9): 1309-1338.

Lebois, E. P., Jones, C. K., Lindsley, C. W. The Evolution of Histamine H(3) Antagonists/Inverse Agonists. Current Topics in Medicinal Chemistry. 2011, 11 (6): 648-660.

Cheung, Y. Y., Zamorano, R., Bloabaum, A. L.,Weaver, C. D., Conn, P. J., Lindsley, C. W. Niswender, C. M., Hopkins, C. R. Solution-Phase Parallel Synthesis and SAR of Homopiperazinyl Analogs as Positive Allosteric Modulators of mGlu(4). ACS Combinatorial Science. 2011, 13 (2): 159-165.

Williams, R., Manka, J. T., Rodriguez, A. L., Vinson P. N., Niswender, C. M., Weaver, C. D., Jones, C. K., Conn, P. L., Lindsley, C. W., Stauffer, S. R. Synthesis and SAR of centrally active mGlu(5) positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorganic & Medicinal Chemistry Letters. 2011, 21 (5): 1350-1353.

Wood, M.R., Hopkins, C. R., Brogan, J. T., Conn P. J., Lindsley, C. W. Molecular Switches" on mGluR Allosteric Ligands That Modulate Modes of Pharmacology. Biochemistry. 2011, 50 (13): 2403-2410.

Bhave, G., Chauder, B. A., Liu, W., Dawson E. S., Kadakia, R., Nguyen, T. T., Lewis, L. M., Meiler, J., Weaver, C. D., Satlin, L. M., Lindsley, C. W. Denton, J. S. Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel. Molecular Pharmacology. 2011, 79 (1): 42-50.

Kang, D. W., Park, M. H., Lee, Y. J., Kim, H. S., Lindsley, C. W., Brown, H. A., Min, D. S. Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells. International Journal of Cancer. 2011, 128 (4): 805-816.

Engers, D. W., Field, J. R., Le, U., Zhou, Y., Bolinger, J. D., Zamorano, R., Blobaum, A. L., Jones, C. K., Jadhav, S., Weaver, C. D., Conn, P. J., Lindsley, C. W., Niswender, C. M., Hopkins, C. R. Discovery, Synthesis, and Structure-Activity Relationship Development of a Series of N-(4-Acetamido)phenylpicolinamides as Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 (mGlu(4)) with CNS Exposure in Rats. Journal of Medicinal Chemistry. 2011, 54 (4): 1106-1110.

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