[4-1]Therapeutic Perspectives of Allosteric, Biased-Signaling

报告题目：Therapeutic Perspectives of Allosteric, Biased-Signaling

Modulators of the Cannabinoid Receptor One

报 告 人：Prof. Debra Ann Kendall

AAAS (American Association for the Advancement of Science) Fellow

Board of Trustees Distinguished Professor

Department of Pharmaceutical Sciences,University of Connecticut

报告时间：2016年4月1日（星期五）上午10:00
报告地点：独墅湖校区二期云轩楼2301室

报告摘要：
The cannabinoid CB1 receptor, a class A GPCR, binds orthosteric ligands such as CP55940 and D9-THC and triggers Gi-mediated effects. The endogenous cannabinoids, anandamide and 2-acyl glycerol are also orthosteric ligands for CB1. However, the synthetic molecule ORG27569 has been identified as a positive allosteric modulator of CP55940 binding to CB1 yet acts as an antagonist of G protein coupling. The ORG27569-induced conformational change of the CB1 receptor leads to cellular internalization and downstream activation of ERK signaling in a G-protein independent manner that is dependent on beta-arrestin. This provides the first case of allosteric ligand-biased signaling via CB1 in HEK293 and neuronal cells. Moreover, beta-arrestin signaling is correlated with time in intracellular compartments. Allosteric modulators of GPCRs provide a mechanism for fine tuning the response of these receptors selectively for therapeutic uses.

 报告人近期发表论文：

1.      Scott, C.E.,  Ahn, K.H., Graf,S.T., Goddard III, W.A.,Kendall, D.A. and Abrol, R. (2016) Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Cannabinoid Receptor and the Implications for Drug Design, J. Chem. Inf. Model., 56, 201-212; co-corresponding author.

2.      Delgado-Peraza, F., Ahn, K.H., Mungrueh, I.N. Mackie, K., Kendall, D.A. and Yudowski, G.A. (2016) Systems Analysis of β-arrestin Signaling from the CB1R, in press; co-corresponding author.

3.      Lu, D., Dopart, R. and Kendall, D.A. (2016) Controlled Downregulation of the Cannabinoid CB1 Receptor Provides a Promising Approach for the Treatment of Obesity and Obesity-derived Type 2 Diabetes, Cell Stress Chaperon. 21, 1-7.

4.      Picone, R. L. and Kendall, D.A. (2015) From the Bench, Toward the Clinic: Therapeutic Opportunities for Cannabinoid Receptor Modulation, Mol. Endocrinol. 29, 801-813.

5.      Mahmoud, M., Olszewska, T., Liu, H., Shore, D.M., Hurst, D.P., Reggio, P.H., Lu, D. andKendall, D.A. (2015) 4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)(cyclohexyl)methanone hydrochloride (LDK1229): a New Cannabinoid CB1 Receptor Inverse Agonist from the Class of Benzhydryl Piperazine Analogs, Mol. Pharmacol.87, 197-206; includes selected cover design.

6.      Wowor, A.J., Yan, Y., Auclair, S.M., Yu, D., Zhang, J., May, E.R., Gross, M.L., Kendall, D.A. and Cole, J.L. (2014) Analysis of SecA Dimerization in Solution, Biochemistry 53, 3248–3260.

7.      Flores-Otero, J., Ahn, K.H., Delgado-Peraza, F., Mackie, K., Kendall, D.A. and Yudowski, G.A. (2014) Ligand-Specific Endocytic Dwell Times Control Functional Selectivity of the Cannabinoid Receptor 1, Nature Communications 5, 1-11.

8.      Khurana, L., Ali, H.I., Olszewska, T., Ahn, K., Damaraju, A., Kendall, D.A. and Lu, D. (2014) Optimization of Chemical Functionalities of Indole-2-Carboxamides to Improve Allosteric Parameters for the Cannabinoid Receptor 1 (CB1), J. Med. Chem. 57, 3040–3052.

9.      Bhanu, M.K. and Kendall, D.A. (2014) Fluorescence Spectroscopy of Soluble E. Coli SPaseI 2-75 Reveals Conformational Changes in Response to Ligand Binding, Proteins: Struct., Funct., and Bioinf. 82, 596-606.

10.  Mahmoud, M.M., Ali, H.I., Ahn, K.H., Damaraju, A., Samala, S., Pulipati, V.K., Kolluru, S., Kendall, D.A. and Lu, D. (2013) Structure-Activity Relationship Study of Indole-2-carboxamides Identifies a Potent Allosteric Modulator for the CB1 Receptor, J. Med. Chem. 56, 7965-7975.

11.  Ahn, K.H., Mahmoud, M.M., Shim, J.-Y. and Kendall, D.A. (2013) Distinct Roles of -arrestin 1 and -arrestin 2 in ORG27569-induced Biased Signaling and Internalization of the Cannabinoid Receptor One (CB1), J. Biol. Chem. 288, 9790-9800.

12.  Ahn, K. H., Scott, C. E., Abrol, R., Goddard III, W. A., and Kendall, D. A. (2013) Computationally-predicted CB1 Cannabinoid Receptor Mutants Adopt a Continuum of Constitutive Activity Reflected in G protein Coupling Levels, Thermal Stability and Ligand Binding, Proteins: Struct., Funct., and Bioinf. 81, 1304-1317.

13.  Ahn, K.H., Mahmoud, M.M., Samala, S., Lu, D. and Kendall, D.A. (2013) Profiling Two Indole-2-Carboxamides for Allosteric Modulation of the CB1 Receptor, J. Neurochem.124, 584-589.

14.  Scott, C.E., Abrol, R., Ahn, K.H., Kendall, D.A. and Goddard III, W.A. (2013) Molecular Basis for the Dramatic Changes in Cannabinoid CB1 GPCR Activation upon Single Point Mutations, Prot. Sci. 22, 101-113.