David R. Sibley, Ph.D.

Headshot of David R. Sibley

David R. Sibley, Ph.D.

Senior Investigator
Address
MOLECULAR NEUROPHARMACOLOGY SECTION

BG 35 RM 3A-201
35 CONVENT DR
BETHESDA MD 20814

Dr. Sibley received his B.S. degree in Biology from San Diego State University and his Ph.D. in Physiology/Pharmacology from the University of California, San Diego where he worked with Ian Creese studying the ligand binding properties of dopamine receptors. He subsequently carried out postdoctoral work with Robert Lefkowitz at Duke University where he characterized adrenergic receptor regulatory mechanisms. Dr. Sibley moved to the NINDS in 1987 and was appointed Chief of the Molecular Neuropharmacology Section in 1992. His laboratory is currently investigating the molecular, cellular and biochemical properties of dopamine receptors and their role in neuronal signaling.

The long-term goal of the Molecular Neuropharmacology Section is the characterization of neurotransmitter receptor-mediated information transduction, and its regulation, across neuronal membranes. The primary model systems under investigation are those  receptors that are linked to their signal transduction pathways via guanine nucleotide binding regulatory (G) proteins with specific emphasis on dopamine receptor subtypes. Specific G proteins have been shown to link these receptors to the activation and inhibition of various nucleotide cyclases, phospholipases, and several ion channels. In order to characterize these receptors at the biochemical and molecular levels and study their regulation, there are several ongoing interrelated lines of research.

Ongoing projects include investigating receptor structure/function/pharmacology relationships, receptor-effector coupling mechanisms, G protein and beta-arrestin interactions, and molecular mechanisms of receptor desensitization and intracellular trafficking. We are also interested in using high throughput screening approaches to develop novel ligands for modulating dopamine receptor expression and signaling. These efforts have led to the discovery of allosteric ligands, biased agonists, and best-in-class selective agonists and antagonists of the D1, D2 or D3 dopamine receptor subtypes. These compounds may prove useful as chemical probes as well as novel pharmacological therapies for treating numerous neurological and psychiatric disorders associated with aberrant dopaminergic signaling.

Emmanuel Akano, M.D., Clinical Fellow

Emily Andeson, B.S., Postbaccalaureate Fellow

Carl Ash, B.A., Postbaccalaureate Fellow

Noelia Boldiszar, B.S., Postbaccalaureate Fellow

R. Benjamin Free, Ph.D., Staff Scientist

Kathryn D. Luderman, Ph.D., Research Fellow

Nora Madaras, B.S., Postbaccalaureate Fellow

Amy Moritz, Ph.D., Research Fellow

Ashley Nilson, Ph.D., Postdoctoral Fellow

Mojgan Yazdankhah, M.S., Biologist and Lab Manager

Sibley, D.R., Luderman, K.D., Free, R.B., and Shi, L., Novel cryro-EM structures of the D1 dopamine receptor unlock its therapeutic potential, Signal Transduction and Targeted Therapy, 6(1): 205, 2021.

Bonaventura, Lam, S., Carlton, M., Boehm, Gomez, J.L., Solis-Castrejon, Sanchez-Soto, Morris, P.J., Fredriksson, I., Thomas, C.J., Sibley, D.R., Shaham, Y., Zarate, C.A., and Michaelides, M., Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability, Molecular Psychiatry, Apr 15, 2021.

Aslanoglou, D., Bertera, S., Sánchez-Soto, M., Free, R.B., Lee, J., Zong, W., Xue, X., Shrestha, S., Brissova, M., Logan, R.W., Yechoor, V.K., Sibley, D.R., Botinno, R., and Freyberg, Z., Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors, Translational Psychiatry, 11(1):59, 2021.

Luderman, K.D., Jain, P., Free, R.B., Conroy, J.L., Aubé, J., Sibley, D.R., Frankowski, K.J., Development of pyrimidone D1 dopamine receptor positive allosteric modulators, Bioorganic and Medicinal Chemistry Letters, 31:127696, 2021.

Moritz, A.E., Bonifazi, A., Guerrero, A., Kumar, V., Free, R.B., Lane, J.R., Verma, R.K., Shi, L., Newman, A.H., and Sibley, D.R., Evidence for a stereoselective mechanism for bitopic activity by extended-length antagonists of the Ddopamine receptor, ACS Chemical Neuroscience, 11(20): 3309-3320, 2020. 

Ågren, R., Zeberg, H., Stępniewski, T.M., Free, R.B., Reilly, S.W., Luedtke, R.R., Århem, P., Ciruela, F., Sibley, D.R., Mach, R.H., Salent, J., Nilsson, J., and Sahlholm, K., A ligand with two modes of interaction with the dopamine D2 receptor – an induced-fit mechanism of insurmountable antagonism, ACS Chemical Neuroscience, 11(19): 3130-3143, 2020.

Moritz, A.E., Free, R.B., Weiner, W.S., Akano, E., Gandhi, D., Abramyan, A., Keck, T.M., Ferrer, M., Hu, X., Southall, N., Steiner, J., Aubé, J., Shi, L., Frankowski, K.J., and Sibley, D.R., Discovery, Optimization and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist, Journal of Medicinal Chemistry, 63(10):5526-5567, 2020.

Castello, J., Cortés, M., Malave, L., Kottmann, A., Sibley, D.R., Friedman, E., and Rebholz, H., The dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA-induced dyskinesia, Scientific Reports, Feb 13;10(1):2542, 2020.

Sanchez-Soto, M., Verma, R.K., Willette, B.K.A., Gonye, E.C., Moore, A.M., Moritz, A.E., Yano, H., Free, R.B., Shi, L., and Sibley, D.R., A structural basis for how ligand binding site alterations can allosterically regulate GPCR signaling and engender functional selectivity, Science Signaling, Feb. 4;13(617), 2020.

Bocarsly, M., Silva, D.D.S.E., Kolb, V., Luderman, K.D., Shashikiran, S., Rubinstein, M., Sibley, D.R., Dobbs, L.K., Alvarez, V.A., A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors, Cell Reports, 29 (5): 1147-1163, 2019. 

Bonaventura, J., Eldridge, M.A., Hu, F., Gomez, J.L., Sanchez-Soto, M., Abramyan, A.M., Lam, S., Boehm, M., Ruiz, C., Farrell, M., Shrestha, S.S., Telu, S., Zoghbi., S.S., Gladding, R.L., Moreno, A., Mustafa, I., Faress, G., Andersen, N., Lin, J.Y., Pike, V.W., Innis, R.B., Moaddel, R., Morris, P., Shi, L., Sibley, D.R., Mahler, S.V., Nabavi, S., Pomper, M.G., Bonci, A., Horti, A.G., Richmond, B.J., and Michaelides, M.,  High-potency ligands for DREADD imaging and activation in rodents and monkeys, Nature Communications 10: 4627, 2019.

Keck, T.M., Free, R.B., Day, M.M., Brown, S.L., Maddaluna, M.S., Fountain, G., Cooper, C., Fallon, B., Holmes, M., Stang, C.S., Burkhardt, R., Bonifazi, A., Ellenberger, M., Newman, A.H., Sibley, D.R., Wu, C., and Boateng, C.A., Dopamine D4 receptor-selective compounds reveal structure-activity relationships that engender agonist efficacy, Journal of Medicinal Chemistry, 62(7): 3722-3740, 2019.

Farino, Z.J., Morgenstern, T.J., Maffei, A., Quick, M., De Solis, A.J., Wiriyasermkul, P., Freyberg, R.J., Aslanoglou, D., Sorisio, D., Inbar, B.P., Free, R.B., Donthamsetti, P., Mosharov, E.V., Kellendonk., C., Schwartz, G.J., Sibley, D.R.,Newman, A.H., Schmauss, C., Zeltser, L.M., Moore, H., Harris, P.E., Javitch, J.A., and Freyberg, Z., New roles for dopamine D2 and D3 receptors in pancreatic beta cell insulin secretion. Molecular Psychiatry, 25:2070-2085, 2019.

Luderman, K.D., Conroy, J.L., Free, R.B., Southall, N., Ferrer, M., Sanchez-Soto, M., Moritz, A.E., Willette, B.K.A., Fyfe, T.J., Jain, P., Titus, S., Hazelwood, L.A., Aubé, J., Lane, J.R., Frankowski, K.J., and Sibley, D.R., Identification of positive allosteric modulators of the D1 dopamine receptor that act at diverse binding sites., Molecular Pharmacology, 94: 1197-1209, 2018.

Chun, L.S., Vekariya, R.H., Free, R.B., Li, Y., Lin, D.T., Liu, F., Namkung, Y., Laporte, S.A., Moritz, A.E., Aubé, J., Frankowski, K.J., and Sibley, D.R., Structure-activity investigation of a G protein biased agonist for the D2 dopamine receptor reveals molecular determinants for biased signaling, Frontiers in Synaptic Neuroscience, February 21; 10(2): 1-18, 2018.

Verma, R.K., Abramyan, A.M., Michine, M., Free, R.B., Sibley, D.R., Javitch, J.A., Lane, J.R., and Shi, L., The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors, PLOS Computational Biology, Jan 16;14(1): e1005948, 2018.

Sibley, D.R. and Shi, L., A new era of rationally designed antipsychotics, Nature, 555: 170-172, 2018.

Free, R.B., Clark, J., Amara, S.G., and Sibley, D.R., Neurotransmission in the Central Nervous System, In, Goodman and Gilman’s The Pharmacological Basis of Therapeutics (13th edition), L.L. Brunton (ed.), McGraw Hill, Chapter 14, pp. 243-266, 2018. 

Sibley, D.R., Hazelwood, L.A, Amara, S.G., 5-Hydroxytryptamine (Serotonin) and Dopamine, In, Goodman and Gilman’s The Pharmacological Basis of Therapeutics (13th edition), L.L. Brunton (ed.), McGraw Hill, Chapter 13, pp. 225-242, 2018.

Moritz, A.E., Free, R.B., and Sibley, D.R., Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds, Cellular Signaling, 41: 75-81, 2018.

Carr, G.V., Maltese, F., Sibley, D.R., Weinberger, D.R., and Papaleo, F., The dopamine D5 receptor is critically involved in working memory, Frontiers in Pharmacology, 8: 666, 2017.

Kumar, V., Moritz, A.E., Keck, T.M., Bonifazi, A., Ellenberger, M., Sibley, C.D., Free, B.F., Shi, L., Lane, J.R., Sibley, D.R., and Newman, A.H., Synthesis and pharmacological characterization of a novel series of trans-cyclopropylmethyl-linked 4-phenylpiperazine analogues that exhibit selectivity and allosteric pharmacology at the dopamine D3 receptor (D3R), Journal of Medicinal Chemistry, 60: 1478-1494, 2017.

Zou, M.-F., Keck, T.M., Kumar, V., Donthamsetti, P., Michino, M., Burzynski, C., Schweppe, Bonfazi, A., Free, R.B., Sibley, D.R., Janowsky, A., Shi, L., Javitch, J.A., Newman, A.H., Novel analogs of (R)-5-(methylamino)-5,6,-dhydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (sumanirole) provide clues to dopamine D2/D3 receptor agonist selectivity, Journal of Medicinal Chemistry, 59: 2973-2988, 2016. 

Link to all PubMed publications: https://www.ncbi.nlm.nih.gov/pubmed/?term=sibley+dr