An allosteric modulator to control endogenous G protein-coupled receptors with light.

Controlling drug activity with light offers the possibility of enhancing pharmacological selectivity with spatial and temporal regulation, thus enabling highly localized therapeutic effects and precise dosing patterns. Here we report on the development and characterization of what is to our knowledge the first photoswitchable allosteric modulator of a G protein-coupled receptor. Alloswitch-1 is selective for the metabotropic glutamate receptor mGlu5 and enables the optical control of endogenous mGlu5 receptors.

[1]  J. Faber,et al.  Normal Table of Xenopus Laevis (Daudin) , 1958 .

[2]  B. Erlanger,et al.  Photochromic activators of the acetylcholine receptor. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[3]  C. Cotman,et al.  Growth factor upregulation of a phosphoinositide-coupled metabotropic glutamate receptor in cortical astrocytes , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  J. Bockaert,et al.  Coupling of metabotropic glutamate receptors 2 and 4 to G alpha 15, G alpha 16, and chimeric G alpha q/i proteins: characterization of new antagonists. , 1996, Molecular pharmacology.

[5]  Shigetada Nakanishi,et al.  Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors , 1996, Nature.

[6]  J. Bockaert,et al.  Comparative effect of l-CCG-I, DCG-IV and γ-carboxy-l-glutamate on all cloned metabotropic glutamate receptor subtypes , 1998, Neuropharmacology.

[7]  R. Langer,et al.  Drug delivery and targeting. , 1998, Nature.

[8]  David Robbe,et al.  A simple method to transfer plasmid DNA into neuronal primary cultures: functional expression of the mGlu5 receptor in cerebellar granule cells , 1999, Neuropharmacology.

[9]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[10]  R A John Challiss,et al.  Determinants of Metabotropic Glutamate Receptor-5-mediated Ca2+ and Inositol 1,4,5-Trisphosphate Oscillation Frequency , 2002, The Journal of Biological Chemistry.

[11]  J. M. Mathiesen,et al.  Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB‐1893 and MPEP , 2003, British journal of pharmacology.

[12]  E. Isacoff,et al.  Reversibly caged glutamate: a photochromic agonist of ionotropic glutamate receptors. , 2007, Journal of the American Chemical Society.

[13]  Ehud Y. Isacoff,et al.  Optical Switches for Remote and Noninvasive Control of Cell Signaling , 2008, Science.

[14]  Arthur Christopoulos,et al.  Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders , 2009, Nature Reviews Drug Discovery.

[15]  Dirk Trauner,et al.  Photochromic blockers of voltage-gated potassium channels. , 2009, Angewandte Chemie.

[16]  Brian P. Timko,et al.  Remotely Triggerable Drug Delivery Systems , 2010, Advanced materials.

[17]  G. Miller.  Is pharma running out of brainy ideas? , 2010, Science.

[18]  L. Rajendran,et al.  Subcellular targeting strategies for drug design and delivery , 2010, Nature Reviews Drug Discovery.

[19]  O. Masseck,et al.  Light‐ and drug‐activated G‐protein‐coupled receptors to control intracellular signalling , 2011, Experimental physiology.

[20]  F. Nicoletti,et al.  Metabotropic glutamate receptors: From the workbench to the bedside , 2011, Neuropharmacology.

[21]  P Jeffrey Conn,et al.  "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. , 2011, Biochemistry.

[22]  Anna L. Blobaum,et al.  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. , 2011, Journal of medicinal chemistry.

[23]  Arup K. Ghose,et al.  Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery , 2011, ACS chemical neuroscience.

[24]  Dirk Trauner,et al.  Rapid optical control of nociception with an ion channel photoswitch , 2012, Nature Methods.

[25]  D. Raines,et al.  Azo-propofols: photochromic potentiators of GABA(A) receptors. , 2012, Angewandte Chemie.

[26]  D. Trauner,et al.  A photoswitchable neurotransmitter analogue bound to its receptor. , 2013, Biochemistry.

[27]  H. Adesnik,et al.  Optogenetic pharmacology for control of native neuronal signaling proteins , 2013, Nature Neuroscience.

[28]  E. Giralt,et al.  Light-regulated stapled peptides to inhibit protein-protein interactions involved in clathrin-mediated endocytosis. , 2013, Angewandte Chemie.

[29]  K. Gregory,et al.  Pharmacology of metabotropic glutamate receptor allosteric modulators: structural basis and therapeutic potential for CNS disorders. , 2013, Progress in molecular biology and translational science.

[30]  A. Schier,et al.  Optical Control of Metabotropic Glutamate Receptors , 2013, Nature Neuroscience.

[31]  T. Gudermann,et al.  Optical control of TRPV1 channels. , 2013, Angewandte Chemie.

[32]  Cody J. Wenthur,et al.  Drugs for allosteric sites on receptors. , 2014, Annual review of pharmacology and toxicology.