title: Small-molecule antagonists of melanopsin-mediated phototransduction.
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 central nervous system responses, including photophobia, sleep, circadian rhythms and neuroendocrine function. Here we describe the identification of a potent synthetic melanopsin antagonist with in vivo activity. New sulfonamide compounds inhibiting melanopsin (opsinamides) compete with retinal binding to melanopsin and inhibit its function without affecting rod- and 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.
authors: 1] Lundbeck Research USA Inc., Paramus, New Jersey, USA. [2].
authors: Kenneth A
authors: KA
authors: Jones
authors: Megumi
authors: M
authors: Hatori
authors: Ludovic S
authors: LS
authors: Mure
authors: Jayne R
authors: JR
authors: Bramley
authors: Roman
authors: R
authors: Artymyshyn
authors: Sang-Phyo
authors: SP
authors: Hong
authors: Mohammad
authors: M
authors: Marzabadi
authors: Huailing
authors: H
authors: Zhong
authors: Jeffrey
authors: J
authors: Sprouse
authors: Quansheng
authors: Q
authors: Zhu
authors: Andrew T E
authors: AT
authors: Hartwick
authors: Patricia J
authors: PJ
authors: Sollars
authors: Gary E
authors: GE
authors: Pickard
authors: Satchidananda
authors: S
authors: Panda
mesh_terms: D006801:Humans; D055537:Light Signal Transduction / Q000187:drug effects*; D015394:Molecular Structure; D017299:Rod Opsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000099210:Melanopsin
chemical_list: D017299:Rod Opsins; D054852:Small Molecule Libraries; D013449:Sulfonamides; D000099210:Melanopsin
references: FASEB J. 2013 Apr;27(4):1572-84
references: 23303210
references: Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1217-21
references: 15653769
references: PLoS One. 2008 Jun 11;3(6):e2451
references: 18545654
references: Trends Mol Med. 2010 Oct;16(10):435-46
references: 20810319
references: Science. 2000 Aug 4;289(5480):739-45
references: 10926528
references: Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10339-44
references: 16014418
references: CMAJ. 1997 May 1;156(9):1273-87
references: 9145054
references: Science. 2005 Jan 28;307(5709):600-4
references: 15681390
references: Neuron. 2005 Dec 22;48(6):1001-10
references: 16364903
references: PLoS Biol. 2010 Dec 07;8(12):e1000558
references: 21151887
references: Nature. 2009 Jan 15;457(7227):281-7
references: 19118382
references: Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):340-5
references: 9419377
references: Science. 2003 Jul 25;301(5632):525-7
references: 12829787
references: Nat Neurosci. 2010 Feb;13(2):239-45
references: 20062053
references: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17374-8
references: 20855606
references: Nature. 2005 Feb 17;433(7027):741-5
references: 15674244
references: Pflugers Arch. 2007 Aug;454(5):849-55
references: 17351786
references: Nature. 2005 Feb 17;433(7027):745-9
references: 15674243
references: Nat Neurosci. 2001 Jun;4(6):621-6
references: 11369943
references: Neuron. 2010 May 13;66(3):417-28
references: 20471354
references: Science. 2003 Jan 10;299(5604):245-7
references: 12522249
references: Neuron. 2001 Mar;29(3):749-55
references: 11301033
references: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20356-61
references: 18077393
references: J Neurosci. 2007 Dec 5;27(49):13468-80
references: 18057205
references: Headache. 1991 Sep;31(8):533-6
references: 1960058
references: Physiol Rev. 2010 Oct;90(4):1547-81
references: 20959623
references: Nature. 2011 Mar 31;471(7340):651-5
references: 21389988
references: J Mol Biol. 2004 Sep 10;342(2):571-83
references: 15327956
references: Trends Pharmacol Sci. 1993 Mar;14(3):89-91
references: 8488569
references: Cell Mol Life Sci. 2007 Jan;64(2):144-54
references: 17160354
references: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8861-5
references: 18579788
references: Nature. 2011 Mar 31;471(7340):656-60
references: 21389983