Douglas Sheffler's Research Focus
Dr. Sheffler joined the Sanford Burnham Prebys faculty in September 2012. Prior to this, he was a Research Assistant Professor at Vanderbilt University in the laboratory of P. Jeffrey Conn (2010-2012), where he also performed post-doctoral work (2006-2010). Dr. Sheffler has over 15 years’ experience in the study of G-protein coupled receptor (GPCR) signaling, assay development, high throughput screening for novel GPCR ligands, cell biology, neuroscience, and pharmacology. His interests are in the complex regulation of GPCRs: their signal transduction, ligand binding, receptor desensitization, and the processes of GPCR internalization and down-regulation. In addition, he has also has a specific interest in both the pharmacology of GPCRs, in general mechanisms of signal transduction, and in the pathogenesis of schizophrenia. During his graduate studies at Case Western Reserve University in the laboratory of Bryan L. Roth, M.D., Ph.D., he discovered the regulation of 5-HT2A serotonin receptor signal transduction by p90 ribosomal S6 kinase (RSK2). During his post-doctoral studies and work as a Research Assistant Professor at Vanderbilt University, he focused on the discovery and characterization of orthosteric and allosteric modulators of GPCRs and led pharmacology efforts characterizing novel M1 muscarinic acetylcholine receptor agonists and antagonists, M1 positive allosteric modulators (PAMs), Glycine Transporter Type 1 (GlyT1) inhibitors, and novel Group II metabotropic glutamate receptor (mGlu) PAMs and NAMs. Dr. Sheffler’s research has resulted in more than 45 journal articles and is a listed inventor on five patent applications pertaining to small molecule therapeutics. Dr. Sheffler received a NARSAD Young Investigator Award in 2013 from the Brain and Behavior Research Foundation.
Douglas Sheffler's Research Report
The metabotropic glutamate receptors (mGlus) are G protein-coupled receptors (GPCRs) that play numerous roles in modulating synaptic transmission and cell excitability. Recent preclinical and clinical studies provide strong evidence that agonists of the group II mGlus, comprised of the mGlu2 and mGlu3 subtypes, may provide a novel approach to treatment of schizophrenia and anxiety disorders. Based on this, there has been a major focus on understanding the roles of these receptors in regulating transmission in forebrain and limbic circuits. However, currently available orthosteric (glutamate site) agonists activate both mGlu2 and mGlu3 and do not provide insight into which subtype is most important for clinical efficacy. Alternatively, recent focus on compounds interacting with less highly conserved allosteric sites has led to advances in subtype selective compound development. Dr. Sheffler and others have discovered and characterized highly selective mGlu2 positive allosteric modulators (PAMs), that have no effect on mGlu3, and these compounds have allowed us to elucidate many of the physiological roles of mGlu2. These PAMs do not activate the receptor directly but act allosterically to potentiate glutamate responses. Dr. Sheffler and collaborators have also discovered group II mGlu negative allosteric modulators (NAMs) and have very recently discovered the first highly selective antagonist of mGlu3. The development of these pharmacological tools provides an opportunity to fully elucidate the roles of these mGlu subtypes. The group II mGlus play important roles in regulating transmission through the hippocampal formation. For example, activation of presynaptic group II mGlus reduces transmission at numerous hippocampal synapses including perforant path-dentate gyrus synapses and the mossy fiber synapse. In contrast, presynaptic group II mGlus are not involved in directly regulating transmission at the Schaffer collateral - CA1 (SC-CA1) synapse. However, we have previously reported extensive studies demonstrating group II mGlu involvement in a novel form of glial-neuronal communication in hippocampal area CA1. When coincidentally activated with β-adrenergic receptors (βARs) in astrocytes, group II mGlus induce a marked potentiation of cAMP responses elicited by activation of βARs. This synergistic increase in glial cAMP accumulation results in the release of adenosine, which activates presynaptic A1 adenosine receptors on neighboring SC terminals and induces a profound depression of transmission at the SC-CA1 synapse. This novel form of glial-neuronal signaling may provide a protective mechanism to reduce the risk of excitotoxicity when there is excessive excitatory drive to the hippocampus, such as during periods of intense or prolonged stress. This potential role has implications relevant for the therapeutic effects of group II mGlu agonists and is consistent with multiple studies suggesting group II mGlu agonists can reduce both acute and long term responses to stress. We have postulated that this effect is mediated by mGlu3 based on heavy expression of mGlu3 in hippocampal astrocytes. However, until now, selective reagents that differentiate between mGlu2 and mGlu3 have not been available to rigorously determine the specific group II mGlu subtype involved. The long term goal of Dr. Sheffler’s research is to establish the relative roles of individual group II mGlu subtypes in mediating glial-neuronal communication and modulating synaptic transmission in the hippocampus using pharmacological, biochemical, and electrophysiological approaches.
Douglas Sheffler's Bio
Dr. Sheffler joined Sanford Burnham Prebys in September 2012.
Post-doctoral Training, Vanderbilt University, Nashville, TN Mentor: Jeffrey Conn, Ph.D. (2005-2010)
Ph.D., Case Western Reserve University, Cleveland, OH Mentor: Bryan Roth, M.D., Ph.D. (1999-2005)
Honors and Recognition
2013 NARSAD Young Investigator Award Brain and Behavior Research Foundation
Design and synthesis of systemically active metabotropic glutamate subtype-2 and -3 (mGlu2/3) receptor positive allosteric modulators (PAMs): pharmacological characterization and assessment in a rat model of cocaine dependence.
Dhanya RP, Sheffler DJ, Dahl R, Davis M, Lee PS, Yang L, Nickols HH, Cho HP, Smith LH, D'Souza MS, Conn PJ, Der-Avakian A, Markou A, Cosford ND
J Med Chem 2014 May 22 ;57(10):4154-72
Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: development of a [3.3.0]-based series and other piperidine bioisosteres.
Sheffler DJ, Nedelcovych MT, Williams R, Turner SC, Duerk BB, Robbins MR, Jadhav SB, Niswender CM, Jones CK, Conn PJ, Daniels RN, Lindsley CW
Bioorg Med Chem Lett 2014 Feb 15 ;24(4):1062-6
Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: development of a potent and CNS penetrant [3.1.0]-based lead.
Jones CK, Sheffler DJ, Williams R, Jadhav SB, Felts AS, Morrison RD, Niswender CM, Daniels JS, Conn PJ, Lindsley CW
Bioorg Med Chem Lett 2014 Feb 15 ;24(4):1067-70
A cellular target engagement assay for the characterization of SHP2 (PTPN11) phosphatase inhibitors.
Romero C, Lambert LJ, Sheffler DJ, De Backer LJS, Raveendra-Panickar D, Celeridad M, Grotegut S, Rodiles S, Holleran J, Sergienko E, Pasquale EB, Cosford NDP, Tautz L
J Biol Chem 2020 Feb 28 ;295(9):2601-2613
A Combination of Flow and Batch Mode Processes for the Efficient Preparation of mGlu<sub>2/3</sub> Receptor Negative Allosteric Modulators (NAMs).
Dhanya RP, Herath A, Sheffler DJ, Cosford NDP
Tetrahedron 2018 Jun 21 ;74(25):3165-3170
Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy.
Barnes SA, Sheffler DJ, Semenova S, Cosford NDP, Bespalov A
Biol Psychiatry 2018 Jun 1 ;83(11):955-962
Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation.
Walker AG, Sheffler DJ, Lewis AS, Dickerson JW, Foster DJ, Senter RK, Moehle MS, Lv X, Stansley BJ, Xiang Z, Rook JM, Emmitte KA, Lindsley CW, Conn PJ
Neuropsychopharmacology 2017 Dec ;42(13):2553-2566
Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[<sup>11</sup>C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2.
Zhang X, Kumata K, Yamasaki T, Cheng R, Hatori A, Ma L, Zhang Y, Xie L, Wang L, Kang HJ, Sheffler DJ, Cosford NDP, Zhang MR, Liang SH
ACS Chem Neurosci 2017 Sep 20 ;8(9):1937-1948
Corrigendum to "Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres" [Bioorg. Med. Chem. Lett. 24 (2014) 1062-1066].
Sheffler DJ, Nedelcovych MT, Williams R, Turner SC, Duerk BB, Robbins MR, Jadhav SB, Niswender CM, Jones CK, Conn PJ, Nathan Daniels R, Lindsley CW
Bioorg Med Chem Lett 2017 May 1 ;27(9):2079