C. David Weaver, Ph.D.

Associate Professor

Faculty Appointments
Associate Professor of Pharmacology Associate Professor of Chemistry
Ph.D., Biochemistry, University of Tennessee, Knoxville, TennesseeB.S., Cell Biology, University of Tennessee, Knoxville, Tennessee
Office Address
824 RRB
2222 Pierce Ave
Nashville, TN 37232
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 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.
Research Keywords
Ion channel pharmacology, high-throughput screening, assay and instrumenation design
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 [print-electronic]. 2011 Jun 6/11/2011; 660(1): 139-47. PMID: 21296065, PMCID: PMC3175485, PII: S0014-2999(11)00089-6, DOI: 10.1016/j.ejphar.2011.01.031, ISSN: 1879-0712.

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 [print-electronic]. 2011 May 5/20/2011; 6(5): 452-65. PMID: 21241068, PMCID: PMC3401128, DOI: 10.1021/cb100305h, ISSN: 1554-8937.

Reid PR, Bridges TM, Sheffler DJ, 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 M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe. Bioorg. Med. Chem. Lett [print-electronic]. 2011 May 5/1/2011; 21(9): 2697-701. PMID: 21194936, PMCID: PMC3082000, PII: S0960-894X(10)01769-5, DOI: 10.1016/j.bmcl.2010.12.015, ISSN: 1464-3405.

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 mGlu4. ACS Comb Sci [print-electronic]. 2011 Mar 3/14/2011; 13(2): 159-65. PMID: 21338051, PMCID: PMC3057427, DOI: 10.1021/co1000508, ISSN: 2156-8944.

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 mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorg. Med. Chem. Lett [print-electronic]. 2011 Mar 3/1/2011; 21(5): 1350-3. PMID: 21315585, PMCID: PMC3498823, PII: S0960-894X(11)00067-9, DOI: 10.1016/j.bmcl.2011.01.044, ISSN: 1464-3405.

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 [print-electronic]. 2011 Feb 2/24/2011; 54(4): 1106-10. PMID: 21247167, PMCID: PMC3166797, DOI: 10.1021/jm101271s, ISSN: 1520-4804.

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 [print-electronic]. 2011 Jan; 79(1): 42-50. PMID: 20926757, PMCID: PMC3014278, PII: mol.110.066928, DOI: 10.1124/mol.110.066928, ISSN: 1521-0111.

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 [print-electronic]. 2010 Dec; 78(6): 1105-23. PMID: 20923853, PMCID: PMC2993468, PII: mol.110.067207, DOI: 10.1124/mol.110.067207, ISSN: 1521-0111.

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 [print-electronic]. 2010 Sep 9/1/2010; 20(17): 5175-8. PMID: 20667732, PMCID: PMC2922490, PII: S0960-894X(10)00951-0, DOI: 10.1016/j.bmcl.2010.07.007, ISSN: 1464-3405.

Lewis M, Weaver CD, McClain MS. Identification of Small Molecule Inhibitors of Clostridium perfringens e-Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen. Toxins (Basel). 2010 Jul 7/1/2010; 2(7): 1825-47. PMID: 20721308, PMCID: PMC2922765, DOI: 10.3390/toxins2071825, ISSN: 2072-6651.

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 [print-electronic]. 2010 Apr 4/21/2010; 1(4): 288-305. PMID: 20414370, PMCID: PMC2857954, DOI: 10.1021/cn9000389, ISSN: 1948-7193.

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 [print-electronic]. 2010 Mar; 77(3): 459-68. PMID: 20026717, PMCID: PMC2835423, PII: mol.109.058768, DOI: 10.1124/mol.109.058768, ISSN: 1521-0111.

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 [print-electronic]. 2009 Dec 12/1/2009; 19(23): 6502-6. PMID: 19875287, PMCID: PMC3177597, PII: S0960-894X(09)01470-X, DOI: 10.1016/j.bmcl.2009.10.059, ISSN: 1464-3405.

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 [print-electronic]. 2009 Dec 12/1/2009; 19(23): 6623-6. PMID: 19854049, PMCID: PMC2801349, PII: S0960-894X(09)01425-5, DOI: 10.1016/j.bmcl.2009.10.024, ISSN: 1464-3405.

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 [print-electronic]. 2009 Nov; 76(5): 1094-103. PMID: 19706730, PMCID: PMC2774996, PII: mol.109.059840, DOI: 10.1124/mol.109.059840, ISSN: 1521-0111.

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 [print-electronic]. 2009 Sep 9/1/2009; 19(17): 4967-70. PMID: 19640716, PMCID: PMC2752865, PII: S0960-894X(09)01033-6, DOI: 10.1016/j.bmcl.2009.07.072, ISSN: 1464-3405.

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. 2009 Jul 7/23/2009; 52(14): 4115-8. PMID: 19469556, PMCID: PMC2765192, DOI: 10.1021/jm9005065, ISSN: 1520-4804.

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 [print-electronic]. 2009 Jun 6/15/2009; 19(12): 3209-13. PMID: 19443219, PMCID: PMC3177605, PII: S0960-894X(09)00621-0, DOI: 10.1016/j.bmcl.2009.04.110, ISSN: 1464-3405.

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. 2009 Jun 6/11/2009; 52(11): 3445-8. PMID: 19438238, PMCID: PMC3875304, DOI: 10.1021/jm900286j, ISSN: 1520-4804.

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 [print-electronic]. 2009 Mar; 75(3): 577-88. PMID: 19047481, PMCID: PMC2684909, PII: mol.108.052886, DOI: 10.1124/mol.108.052886, ISSN: 1521-0111.

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. 2009; 9(13): 1217-26. PMID: 19807667, PII: CTMC-Abs-011-9-13, ISSN: 1873-4294.

Kennedy JP, Williams L, Bridges TM, Daniels RN, Weaver D, Lindsley CW. Application of combinatorial chemistry science on modern drug discovery. J Comb Chem [print-electronic]. 2008 May; 10(3): 345-54. PMID: 18220367, DOI: 10.1021/cc700187t, ISSN: 1520-4774.

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 [print-electronic]. 2008 Jan; 4(1): 42-50. PMID: 18059262, PII: nchembio.2007.55, DOI: 10.1038/nchembio.2007.55, ISSN: 1552-4469.

Lindsley CW, Weaver D, Jones C, Marnett L, Conn PJ. Preclinical drug discovery research and training at Vanderbilt. ACS Chem. Biol. 2007 Jan 1/23/2007; 2(1): 17-20. PMID: 17243778, DOI: 10.1021/cb6004867, ISSN: 1554-8937.

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 [print-electronic]. 2005 Apr; 313(1): 250-9. PMID: 15608074, PII: jpet.104.078592, DOI: 10.1124/jpet.104.078592, ISSN: 0022-3565.

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. 2005 Jan 1/17/2005; 15(2): 363-6. PMID: 15603955, PII: S0960-894X(04)01304-6, DOI: 10.1016/j.bmcl.2004.10.065, ISSN: 0960-894X.

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. 2004 Dec; 9(8): 671-7. PMID: 15634793, PII: 9/8/671, DOI: 10.1177/1087057104268749, ISSN: 1087-0571.

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. 2004 Sep 9/6/2004; 14(17): 4533-7. PMID: 15357987, PII: S0960894X04007899, DOI: 10.1016/j.bmcl.2004.06.035, ISSN: 0960-894X.

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. 2004 Apr 4/19/2004; 14(8): 1991-5. PMID: 15050644, PII: S0960894X04000812, DOI: 10.1016/j.bmcl.2004.01.069, ISSN: 0960-894X.

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. 2004 Jan 1/12/2004; 1(1): 67-76. PMID: 15832502, ISSN: 1543-8384.

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. 2003 Aug 8/28/2003; 46(18): 3778-81. PMID: 12930139, DOI: 10.1021/jm034111v, ISSN: 0022-2623.

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. 2003 Jul 7/17/2003; 46(15): 3197-200. PMID: 12852750, DOI: 10.1021/jm034073f, ISSN: 0022-2623.

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. 1998 Oct; 54(4): 639-46. PMID: 9765506, ISSN: 0026-895X.

Weaver CD, Yao TL, Powers AC, Verdoorn TA. Differential expression of glutamate receptor subtypes in rat pancreatic islets. J. Biol. Chem. 1996 May 5/31/1996; 271(22): 12977-84. PMID: 8662728, ISSN: 0021-9258.

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. 1995 Nov 11/10/1995; 270(45): 27051-7. PMID: 7592955, ISSN: 0021-9258.

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. 1994 Jul 7/8/1994; 269(27): 17858-62. PMID: 7517934, ISSN: 0021-9258.

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. 1993 Feb 2/23/1993; 32(7): 1695-706. PMID: 8439535, ISSN: 0006-2960.

Weaver CD, Roberts DM. Determination of the site of phosphorylation of nodulin 26 by the calcium-dependent protein kinase from soybean nodules. Biochemistry. 1992 Sep 9/22/1992; 31(37): 8954-9. PMID: 1390682, ISSN: 0006-2960.

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. 1991 Jan; 95(1): 222-7. PMID: 16667955, PMCID: PMC1077509, ISSN: 0032-0889.

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. 1990 Aug; 2(8): 678-83. PMID: 2282367, ISSN: 1043-4674.