Professor of Pharmacology & Chemistry
Ph.D., UCSB
craig.lindsley@vanderbilt.edu
Lindsley Research Group

Research Description

The major focus of the Lindsley laboratory is drug discovery and medicinal chemistry. Students in my 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 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 a member of ther Vanderbilt Institutue of Chemical Biology, 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 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 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.

The third area of interest in my group is synthetic organic chemistry. Students will have the opportunity to work on synthetic methodology projects as well as partial and total synthesis projects.

Selected Publications

Conn P.J., Jones C.K., Lindsley C.W. Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends in Pharmacological Sciences. 2009, 30 (3): 148-155.

Lavieri R., Scott S.A., Lewis J.A., Selvy P.E., Armstrong M.D., Brown H.A., Lindsley C.W. Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity. Bioorganic & Medicinal Chemistry Letters. 2009, 19 (8): 2240-2243.

Engers D.W., Rodriguez A.L., Williams R., Hammond A.S., Venable D., Oluwatola O., Sulikowski G.A., Conn P.J., Lindsley C.W. Synthesis, SAR and Unanticipated Pharmacological Profiles of Analogues of the mGluR5 Ago-potentiator ADX-47273. Chemmedchem. 2009, 4 (4): 505-511.

Niswender C.M.; Lebois E.P.; Luo Q.W.; Kim K.; Muchalski H.; HY.; Conn P.J.; Lindsley C.W. Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d] pyrimidines as novel mGluR4 positive allosteric modulators. Bioorganic & Medicinal Chemistry Letters. 2008, 18(20): 5626-5630.

Niswender C.M.; Johnson K.A.; Weaver C.D.; Jones C.K.; Xiang Z.X.; Luo Q.W.; Rodriguez A.L.; Marlo J.E.; de Paulis T.; Thompson A.D.; Days E.L.; Nalywajko T.; Austin C.A.; Williams M.B.; Ayala J.E.; Williams R.; Lindsley C.W.; Conn P.J. Discovery, Characterization, and Antiparkinsonian Effect of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4. Molecular Pharmacology. 2008, 74(5): 1345-1358.

Kennedy J.P.; Brogan J.T.; Lindsley C.W. Total Synthesis and Biological Evaluation of the Marine Bromopyrrole Alkaloid Dispyrin: Elucidation of Discrete Molecular Targets with Therapeutic Potential. Journal of Natural Products. 2008, 71(10): 1783-1786.

Brady A.E.; Jones C.K.; Bridges T.M.; Kennedy J.P.; Thompson A.D.; Heiman J.U.; Breininger M.L.; Gentry P.R.; Yin H.Y.; Jadhav S.B.; Shirey J.K.; Conn P.J.; Lindsley C.W. Centrally Active Allosteric Potentiators of the M-4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats. Journal of Pharmacology and Experimental Therapeutics. 2008, 327(3): 941-953.

Zhao, Z.; Wisnoski, D.D.; O’Brien, J.A.; Lemiare, W.; Williams, Jr., D.L.; Jacobson, M.A.; Wittman, M.; Ha, S.; Schaffhauser, H.; Sur, C.; Pettibone, D.J.; Duggan, M.E.; Conn, P.J.; Hartman, G.D.; Lindsley, C.W. Challlenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA. Bioorganic and Medicinal Chemistry Letters. 2007, 17: 1386-1390.

Pawluczyk, J.M.; McClain, R.T.; Denicola, C.; Mulhearn, J.J.; Rudd, D.J.; Lindsley, C.W. Microwave-initiated living free radical polymerization: Optimization of the preparative scale synthesis of Rasta resins. Tetrahedron Letters. 2007, 48: 1497-1501.

Linsley, Craig W.; Barnett, Stanley F.; Yarochak, Melissa, Bilodeau, Mark T.; Layton, Mark E. Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Current Topics in Medicinal Chemistry. 2007, 7(14): 1349-63.

Linsley, Craig W. Emerging from the shadow of Vioxx. Current Topics in Medicinal Chemistry. 2007, 7(7): 739.

Linsley, C.W.; Weaver, D.; Jones, C.; Marnett, L.; Conn, P.J. Preclinical drug discovery research and training at Vanderbilt. ACS Chemical Biology. 2007, 2(1): 17-20.

Daniels, R Nathan, Linsley, Criag W. A new, non-SSRI mechanism of action for Prozac. Current Topics in Medicinal Chemistry. 2007, 7(10): 1039.

Lindsley, C.W.; Weaver, D.; Conn, P.J.; Marnett, L. Preclinical Drug Discovery Research and Training at Vanderbilt. ACS Chemical Biology. 2007, 2(1): 17-22.

Wolkenberg, S.E.; Zhao, Z.; Kapitskaya, M.; Webber, A.L.; Pertukhin, K.; Tang, Y.S.; Dean, D.C.; Hartman, George D.; Lindsley, C.W. Identification of potent agonists of Photoreceptor-Specific Nuclear Receptor (NR2E3) and preparation of a radioligand. Bioorganic and Medicinal Chemistry Letters. 2006, 16: 5001-5004.

Shipe, W.D.; Yang, F.; Zhao, Z.; Wolkenberg, S.E.; Nolt, M.B.; Lindsley, C.W. Convenient and general microwave-assisted protocols for the expedient synthesis of heterocycles. Heterocycles. 2006, 70: 665-689.

Nolt, M.B.; Smiley, M.A.; Varga, S.L.; McClain, R.T.; Wolkenberg, S.E.; Lindsley, C.W. Convenient preparation of substituted 5-amino oxazoles via a microwave-assisted Cornforth rearrangement. Tetrahedron. 2006, 62: 4698-4704.

Lindsley, C.W.;Wolkenberg, S.E.; Kinney, G.G. Progress in the preparation and testing of glycine transporter type-1 (GlyT1) inhibitors. Current Topics in Medicinal Chemistry. 2006, 8: 1883-1896.

Lindsley, C.W.; Zhao, Z.; Leister, W.H.; OBrien, J.A.; Lemiare, W.; Williams, Jr., D.L.; Chen, T-B.; Chang, R.S.L.;Burno, M.; Jacobson, M.A.; Sur, C.; Kinney, G.G.; Pettibone, D.J.; Tiller,P.R.; Smith, S.;Tsou, N.N.; Duggan, M.E.; Conn, P.J.; Hartman, G.D. Design, synthesis and in vivo efficacy of novel glycine transporter-1 (GlyT1) inhibitors derived from a series of [4-Phenyl-1-(propylsulfonyl)piperidin-4-yl] methyl benzamides. ChemMedChem. 2006, 1: 807-811.

Lindsley, C.W.; Shipe, W.D.; Wolkenberg, S.E.; Theberge, C.R.; Williams, D.L. Jr.; Sur, C.; Kinney, G.G. Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Current Topics in Medicinal Chemistry. 2006, 6: 771-785.

Kausik,K.N.; Nolt, M.B.; Cato, M.J.; Kane, S.A.; Kiss, L.; Spencer, R.H.; Jixin Wang, J.; Lynch, J.L.; Regan, C.P.; Stump, G.L.; Li, B.;White, R.; Yeh, S.; Bogusky, M.J.; Bilodeau, M.T.; Dinsmore, C.J.; Lindsley, C.W.; Hartman, G.D.; Scott Wolkenberg S.E.;Trotter, B.W. Potent antagonists of the atrial IKur/Kv1.5 potassium channel: synthesis and evaluation of analogous N,N- diisopropyl-2-(pyridine-3-yl)acetamides. Bioorganic and Medicinal Chemistry Letters. 2006, 16: 5897-5861.

Lindsley, C.W.; Bogusky, M.J.; Leister, W.H.; McClain, R.T.; Robinson, R.; Barnett, S.F.; Defeo-Jones, D.; III Ross, C.W.; Hartman, G.D. Synthesis and biological evaluation of unnatural canthine alkaloids. Tetrahedron Letters. 2005, 46: 2779-2782.

Kinney, G.G.; O’Brien, Lemaire, W.; Burno, M.’ Bickel, D.J.; Clements, M.K.; Wisnoski, D.D.; Lindsley, C.W.; Tiller, P.R.; Smith, S.; Jacobson, M.A.; Sur, C.; Duggan, M.E.; Pettibone, D.J.; Williams, Jr., D.W. A novel selective allosteric modulator of metabotropic glutamate receptor subtype 5 (mGluR5) has an antipsychotic profile in rat behavioral models. Journal of Pharmacology and Experimental. 2005, 313: 199-211.

Kim, D.; Cheng, G.Z.; Lindsley, C.W.; Yang, H.; Cheng, J.Q. The Akt/PKB pathway: molecular target for cancer therapy. Oncogene. 2005, 24: 7482-7492.

Defeo-Jones, D.; Barnett, S.F.; Fu, S.; Hancock, P.J.; Haskell, K.M.; Leander, K.R.; McAvoy, E.; Robinson, R.G.; Duggan, M.E.; Lindsley, C.W.; Zhao, Z.; Huber, H.E.; Jones, R.E. Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members. N/A. 2005, 4: 271-278.

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