Vanderbilt University School of Medicine

Weaver, Charles David , Ph.D.
Assistant Professor of Pharmacology

Lab Url: N/A

Phone Number: (615) 936-6461


Weaver, Charles's picture

Office Address   Mailing Address

461 PRB

824 RRB 2222 Pierce Ave 37232

Research Keywords
Ion Channel,Drug Discovery,Malaria,Neuroscience,Pharmacology,Receptor,Signal transduction

Research Specialty
Ion channel pharmacology, high-throughput screening, assay and instrumenation design

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.

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.

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.

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.

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.

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.

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. PMCID:2922765

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. PMCID:2922765

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. PMCID:2857954

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. PMCID:2835423

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.

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.

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. PMCID:2765192

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. PMCID:2765192

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. PMCID:2801349

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. PMCID:2774996

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. PMCID:2684909

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. PMCID:2765192

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. PMCID:2801349

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. PMCID:2752865

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. PMCID:2835423

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.

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.

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.

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.

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.

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. PMCID:2684909

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. PMCID:2684909

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<-->two-dimer equilibrium. Biochemistry, 32(7), 1695-706, 1993. PMCID:2684909

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. PMCID:2684909

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. PMCID:1077509

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. PMCID:1077509

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