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      Small molecule antagonists of melanopsin-mediated phototransduction

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          Abstract

          Melanopsin, expressed in a subset of retinal ganglion cells, mediates behavioral adaptation to ambient light and other non-image forming photic responses. This has raised the possibility that pharmacological manipulation of melanopsin can modulate several CNS responses including photophobia, sleep, circadian rhythms and neuroendocrine function. Here we describe the identification of a potent synthetic melanopsin antagonist with in vivo activity. Novel sulfonamide compounds inhibiting melanopsin (opsinamides) compete with retinal binding to melanopsin and inhibit its function without affecting rod/cone mediated responses. In vivo administration of opsinamides to mice specifically and reversibly modified melanopsin-dependent light responses including the pupillary light reflex and light aversion. The discovery of opsinamides raises the prospect of therapeutic control of the melanopsin phototransduction system to regulate light-dependent behavior and remediate pathological conditions.

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          Most cited references32

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          Crystal structure of rhodopsin: A G protein-coupled receptor.

          Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structural features, including a bundle of seven transmembrane alpha helices connected by six loops of varying lengths. We determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution. The highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the seven-helix transmembrane motif. The ground-state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Interactions of the chromophore with a cluster of key residues determine the wavelength of the maximum absorption. Changes in these interactions among rhodopsins facilitate color discrimination. Identification of a set of residues that mediate interactions between the transmembrane helices and the cytoplasmic surface, where G-protein activation occurs, also suggests a possible structural change upon photoactivation.
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            Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice.

            In the mammalian retina, a small subset of retinal ganglion cells (RGCs) are intrinsically photosensitive, express the opsin-like protein melanopsin, and project to brain nuclei involved in non-image-forming visual functions such as pupillary light reflex and circadian photoentrainment. We report that in mice with the melanopsin gene ablated, RGCs retrograde-labeled from the suprachiasmatic nuclei were no longer intrinsically photosensitive, although their number, morphology, and projections were unchanged. These animals showed a pupillary light reflex indistinguishable from that of the wild type at low irradiances, but at high irradiances the reflex was incomplete, a pattern that suggests that the melanopsin-associated system and the classical rod/cone system are complementary in function.
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              Melanopsin is required for non-image-forming photic responses in blind mice.

              Although mice lacking rod and cone photoreceptors are blind, they retain many eye-mediated responses to light, possibly through photosensitive retinal ganglion cells. These cells express melanopsin, a photopigment that confers this photosensitivity. Mice lacking melanopsin still retain nonvisual photoreception, suggesting that rods and cones could operate in this capacity. We observed that mice with both outer-retinal degeneration and a deficiency in melanopsin exhibited complete loss of photoentrainment of the circadian oscillator, pupillary light responses, photic suppression of arylalkylamine-N-acetyltransferase transcript, and acute suppression of locomotor activity by light. This indicates the importance of both nonvisual and classical visual photoreceptor systems for nonvisual photic responses in mammals.
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                Author and article information

                Journal
                101231976
                32624
                Nat Chem Biol
                Nat. Chem. Biol.
                Nature chemical biology
                1552-4450
                1552-4469
                6 September 2013
                25 August 2013
                October 2013
                01 April 2014
                : 9
                : 10
                : 10.1038/nchembio.1333
                Affiliations
                [1 ]Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652
                [2 ]Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010, North Torrey Pines Road, La Jolla, CA 92037
                [3 ]School of Veterinary Medicine and Biomedical Sciences, University of Nebraska, Lincoln, NE 68583
                [4 ]College of Optometry, The Ohio State University, Columbus, OH 43210
                [5 ]Cyanaptic LLC, 16 School Street, Stonington, CT 06378
                [6 ]Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198
                Author notes
                Correspondence, Kenneth A. Jones, kenjones120@ 123456gmail.com , Satchidananda Panda, satchin@ 123456salk.edu
                [*]

                These authors contributed equally to this work.

                Article
                NIHMS512442
                10.1038/nchembio.1333
                3839535
                23974117
                9312aae7-2185-477c-9330-2132552a4da4

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                History
                Funding
                Funded by: National Center for Research Resources : NCRR
                Award ID: S10 RR027450 || RR
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R21 NS066457 || NS
                Funded by: National Eye Institute : NEI
                Award ID: R01 EY017809 || EY
                Funded by: National Eye Institute : NEI
                Award ID: R01 EY016807 || EY
                Categories
                Article

                Biochemistry
                Biochemistry

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