Department of Pharmacology

Faculty

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Charles David Weaver, Ph.D.

Assistant Professor of Pharmacology
BRET Profile (opens in a new window)
david.weaver@Vanderbilt.Edu
(615) 936-6461
Fax: 615-936-6461
461 PRB
Nashville, TN 37232

Education

Post-doctoral, Vanderbilt University
Ph.D., Univ of Tennessee Knoxville
B.S., Univ of Tennessee Knoxville

Research Keywords

Ion Channel,Drug Discovery,Malaria

Research Description

My research is focused on the discovery and characterization of novel chemical tools for studying ion channel structure, function, and therapeutic potential.

Specifically, the projects in my lab are focused on two key roles of ion channels in medicine and public health. The first project area deals with development of drug-like chemical tools for evaluating the role of ligand and voltage-activated potassium channels for the treatment of pain, one the largest unmet medical needs. Recent discoveries in the laboratory are paving the way for the field's first opportunites to evaluate a novel ion channel pain target.

The second project area deals with the development of novel insecticides to aid in the control of malaria and other mosquito-born illnesses that infect nearly half a billion and kill over 1 million people every year. Another recent advancement in high-throughput ion channel assay technology from the laboratory is now making it possibly to rapidly discover and develop novel insecticide to combat the resistance that has developed in insects to the insecticides that were so effective in helping erradicate malaria from the United States and Australia in the middle of the 20th century.

The techniques most most commonly used in the laboratory are plate-based fluorescent assays of ion channel function, automated high-throughput screening, and whole-cell electrophysiology. My laboratory collaborates closely with medicinal chemists, imformaticians, structural biologists, engineers, and software developers.

Publications

Williams, R, Manka, JT, Rodriguez, AL, Vinson, PN, Niswender, CM, Weaver, CD, Jones, CK, Conn, PJ, Lindsley, CW, Stauffer, SR. Synthesis and SAR of centrally active mGlu(5) positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorg Med Chem Lett, 21(5), 1350-3, 2011

Pantel, J, Williams, SY, Mi, D, Sebag, J, Corbin, JD, Weaver, CD, Cone, RD. Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay. Eur J Pharmacol, 2011

Bhave, G, Chauder, BA, Liu, W, Dawson, ES, Kadakia, R, Nguyen, TT, Lewis, LM, Meiler, J, Weaver, CD, Satlin, LM, Lindsley, CW, Denton, JS. Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel. Mol Pharmacol, 79(1), 42-50, 2011

Stoops, SL, Pearson, AS, Weaver, C, Waterson, AG, Days, E, Farmer, C, Brady, S, Weaver, CD, Beauchamp, RD, Lindsley, CW. Identification and Optimization of Small Molecules That Restore E-Cadherin Expression and Reduce Invasion in Colorectal Carcinoma Cells. ACS Chem Biol, 2011

Cheung, YY, Zamorano, R, Blobaum, AL, Weaver, CD, Conn, PJ, Lindsley, CW, Niswender, CM, Hopkins, CR. Solution-Phase Parallel Synthesis and SAR of Homopiperazinyl Analogs as Positive Allosteric Modulators of mGlu(4). ACS Comb Sci, 2011

Engers, DW, Field, JR, Le, U, Zhou, Y, Bolinger, JD, Zamorano, R, Blobaum, AL, Jones, CK, Jadhav, S, Weaver, CD, Conn, PJ, Lindsley, CW, Niswender, CM, Hopkins, CR. 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. J Med Chem, 54(4), 1106-10, 2011

Lewis, M, Weaver, CD, McClain, MS. Identification of Small Molecule Inhibitors of Clostridium perfringens I?-Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen. Toxins (Basel), 2(7), 1825-1847, 2010

Engers, DW, Gentry, PR, Williams, R, Bolinger, JD, Weaver, CD, Menon, UN, Conn, PJ, Lindsley, CW, Niswender, CM, Hopkins, CR. Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS). Bioorg Med Chem Lett, 20(17), 5175-8, 2010

Niswender, CM, Johnson, KA, Miller, NR, Ayala, JE, Luo, Q, Williams, R, Saleh, S, Orton, D, Weaver, CD, Conn, PJ. Context-dependent pharmacology exhibited by negative allosteric modulators of metabotropic glutamate receptor 7. Mol Pharmacol, 77(3), 459-68, 2010

Rodriguez, AL, Grier, MD, Jones, CK, Herman, EJ, Kane, AS, Smith, RL, Williams, R, Zhou, Y, Marlo, JE, Days, EL, Blatt, TN, Jadhav, S, Menon, UN, Vinson, PN, Rook, JM, Stauffer, SR, Niswender, CM, Lindsley, CW, Weaver, CD, Conn, PJ. Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol, 78(6), 1105-23, 2010

Reid, PR, Bridges, TM, Sheffler, DA, Cho, HP, Lewis, LM, Days, E, Daniels, JS, Jones, CK, Niswender, CM, Weaver, CD, Conn, PJ, Lindsley, CW, Wood, MR. Discovery and optimization of a novel, selective and brain penetrant M(1) positive allosteric modulator (PAM): The development of ML169, an MLPCN probe. Bioorg Med Chem Lett, 2010

Mueller, R, Rodriguez, AL, Dawson, ES, Butkiewicz, M, Nguyen, TT, Oleszkiewicz, S, Bleckmann, A, Weaver, CD, Lindsley, CW, Conn, PJ, Meiler, J. Identification of Metabotropic Glutamate Receptor Subtype 5 Potentiators Using Virtual High-Throughput Screening. ACS Chem Neurosci, 1(4), 288-305, 2010

Weaver, CD, Sheffler, DJ, Lewis, LM, Bridges, TM, Williams, R, Nalywajko, NT, Kennedy, JP, Mulder, MM, Jadhav, S, Aldrich, LA, Jones, CK, Marlo, JE, Niswender, CM, Mock, MM, Zheng, F, Conn, PJ, Lindsley, CW. Discovery and development of a potent and highly selective small molecule muscarinic acetylcholine receptor subtype I (mAChR 1 or M1) antagonist in vitro and in vivo probe. Curr Top Med Chem, 9(13), 1217-26, 2009

Zhou, Y, Rodriguez, AL, Williams, R, Weaver, CD, Conn, PJ, Lindsley, CW. Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS. Bioorg Med Chem Lett, 19(23), 6502-6, 2009

Engers, DW, Niswender, CM, Weaver, CD, Jadhav, S, Menon, UN, Zamorano, R, Conn, PJ, Lindsley, CW, Hopkins, CR. Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). J Med Chem, 52(14), 4115-8, 2009

Rodriguez, AL, Williams, R, Zhou, Y, Lindsley, SR, Le, U, Grier, MD, Weaver, CD, Conn, PJ, Lindsley, CW. Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype. Bioorg Med Chem Lett, 19(12), 3209-13, 2009

Williams, R, Johnson, KA, Gentry, PR, Niswender, CM, Weaver, CD, Conn, PJ, Lindsley, CW, Hopkins, CR. Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4). Bioorg Med Chem Lett, 19(17), 4967-70, 2009

Lewis, LM, Bhave, G, Chauder, BA, Banerjee, S, Lornsen, KA, Redha, R, Fallen, K, Lindsley, CW, Weaver, CD, Denton, JS. High-throughput screening reveals a small-molecule inhibitor of the renal outer medullary potassium channel and Kir7.1. Mol Pharmacol, 76(5), 1094-103, 2009

Marlo, JE, Niswender, CM, Days, EL, Bridges, TM, Xiang, Y, Rodriguez, AL, Shirey, JK, Brady, AE, Nalywajko, T, Luo, Q, Austin, CA, Williams, MB, Kim, K, Williams, R, Orton, D, Brown, HA, Lindsley, CW, Weaver, CD, Conn, PJ. Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity. Mol Pharmacol, 75(3), 577-88, 2009

Felts, AS, Saleh, SA, Le, U, Rodriguez, AL, Weaver, CD, Conn, PJ, Lindsley, CW, Emmitte, KA. Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5. Bioorg Med Chem Lett, 19(23), 6623-6, 2009

Bridges, TM, Marlo, JE, Niswender, CM, Jones, CK, Jadhav, SB, Gentry, PR, Plumley, HC, Weaver, CD, Conn, PJ, Lindsley, CW. Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J Med Chem, 52(11), 3445-8, 2009

Kennedy, JP, Williams, L, Bridges, TM, Daniels, RN, Weaver, D, Lindsley, CW. Application of combinatorial chemistry science on modern drug discovery. J Comb Chem, 10(3), 345-54, 2008

Shirey, JK, Xiang, Z, Orton, D, Brady, AE, Johnson, KA, Williams, R, Ayala, JE, Rodriguez, AL, Wess, J, Weaver, D, Niswender, CM, Conn, PJ. An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nat Chem Biol, 4(1), 42-50, 2008

Lindsley, CW, Weaver, D, Jones, C, Marnett, L, Conn, PJ. Preclinical drug discovery research and training at Vanderbilt. ACS Chem Biol, 2(1), 17-20, 2007

L''Heureux, A, Martel, A, He, H, Chen, J, Sun, LQ, Starrett, JE, Natale, J, Dworetzky, SI, Knox, RJ, Harden, DG, Weaver, D, Thompson, MW, Wu, YJ. (S,E)-N-[1-(3-heteroarylphenyl)ethyl]-3-(2-fluorophenyl)acrylamides: synthesis and KCNQ2 potassium channel opener activity. Bioorg Med Chem Lett, 15(2), 363-6, 2005

Tertyshnikova, S, Knox, RJ, Plym, MJ, Thalody, G, Griffin, C, Neelands, T, Harden, DG, Signor, L, Weaver, D, Myers, RA, Lodge, NJ. BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine]: a putative potassium channel opener with bladder-relaxant properties. J Pharmacol Exp Ther, 313(1), 250-9, 2005

Weaver, CD, Harden, D, Dworetzky, SI, Robertson, B, Knox, RJ. A thallium-sensitive, fluorescence-based assay for detecting and characterizing potassium channel modulators in mammalian cells. J Biomol Screen, 9(8), 671-7, 2004

Wu, YJ, Boissard, CG, Chen, J, Fitzpatrick, W, Gao, Q, Gribkoff, VK, Harden, DG, He, H, Knox, RJ, Natale, J, Pieschl, RL, Starrett, JE, Sun, LQ, Thompson, M, Weaver, D, Wu, D, Dworetzky, SI. (S)-N-[1-(4-cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons. Bioorg Med Chem Lett, 14(8), 1991-5, 2004

Wu, YJ, Sun, LQ, He, H, Chen, J, Starrett, JE, Dextraze, P, Daris, JP, Boissard, CG, Pieschl, RL, Gribkoff, VK, Natale, J, Knox, RJ, Harden, DG, Thompson, MW, Fitzpatrick, W, Weaver, D, Wu, D, Gao, Q, Dworetzky, SI. Synthesis and KCNQ2 opener activity of N-(1-benzo[1,3]dioxol-5-yl-ethyl, N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl, and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl acrylamides. Bioorg Med Chem Lett, 14(17), 4533-7, 2004

Faria, TN, Timoszyk, JK, Stouch, TR, Vig, BS, Landowski, CP, Amidon, GL, Weaver, CD, Wall, DA, Smith, RL. A novel high-throughput pepT1 transporter assay differentiates between substrates and antagonists. Mol Pharm, 1(1), 67-76, 2004

Wu, YJ, Davis, CD, Dworetzky, S, Fitzpatrick, WC, Harden, D, He, H, Knox, RJ, Newton, AE, Philip, T, Polson, C, Sivarao, DV, Sun, LQ, Tertyshnikova, S, Weaver, D, Yeola, S, Zoeckler, M, Sinz, MW. Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition. J Med Chem, 46(18), 3778-81, 2003

Wu, YJ, Boissard, CG, Greco, C, Gribkoff, VK, Harden, DG, He, H, L''Heureux, A, Kang, SH, Kinney, GG, Knox, RJ, Natale, J, Newton, AE, Lehtinen-Oboma, S, Sinz, MW, Sivarao, DV, Starrett, JE, Sun, LQ, Tertyshnikova, S, Thompson, MW, Weaver, D, Wong, HS, Zhang, L, Dworetzky, SI. (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide: an orally bioavailable KCNQ2 opener with significant activity in a cortical spreading depression model of migraine. J Med Chem, 46(15), 3197-200, 2003

Weaver, CD, Partridge, JG, Yao, TL, Moates, JM, Magnuson, MA, Verdoorn, TA. Activation of glycine and glutamate receptors increases intracellular calcium in cells derived from the endocrine pancreas. Mol Pharmacol, 54(4), 639-46, 1998

Weaver, CD, Yao, TL, Powers, AC, Verdoorn, TA. Differential expression of glutamate receptor subtypes in rat pancreatic islets. J Biol Chem, 271(22), 12977-84, 1996

Lee, JW, Zhang, Y, Weaver, CD, Shomer, NH, Louis, CF, Roberts, DM. Phosphorylation of nodulin 26 on serine 262 affects its voltage-sensitive channel activity in planar lipid bilayers. J Biol Chem, 270(45), 27051-7, 1995

Weaver, CD, Shomer, NH, Louis, CF, Roberts, DM. Nodulin 26, a nodule-specific symbiosome membrane protein from soybean, is an ion channel. J Biol Chem, 269(27), 17858-62, 1994

Nichols, R, Weaver, CD, Eisenstein, E, Blakley, RL, Appleman, J, Huang, TH, Huang, FY, Howell, EE. Titration of histidine 62 in R67 dihydrofolate reductase is linked to a tetramer&lt;--&gt;two-dimer equilibrium. Biochemistry, 32(7), 1695-706, 1993

Weaver, CD, Roberts, DM. Determination of the site of phosphorylation of nodulin 26 by the calcium-dependent protein kinase from soybean nodules. Biochemistry, 31(37), 8954-9, 1992

Weaver, CD, Crombie, B, Stacey, G, Roberts, DM. Calcium-dependent phosphorylation of symbiosome membrane proteins from nitrogen-fixing soybean nodules : evidence for phosphorylation of nodulin-26. Plant Physiol, 95(1), 222-7, 1991

Roberts, DM, Weaver, CD. How plants respond to stimuli. The Ninth Annual Symposium on Current Topics in Plant Biochemistry and Physiology sponsored by the University of Missouri Interdisciplinary Program in Plant Biochemistry and Physiology, the US Department of Agriculture, and the National Science Foundation, Columbia, MO, USA, April 4-7, 1990. New Biol, 2(8), 678-83, 1990