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Small-molecule antagonists of melanopsin-mediated phototransduction

Nature Chemical Biology volume 9, pages 630–635 (2013)Cite this article

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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 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.

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Figure 1: Opsinamides inhibit melanopsin photoresponse.
Figure 2: Specific and competitive binding of opsinamide to melanopsin.
Figure 3: Opsinamide inhibits melanopsin photoresponses without inhibiting rod and cone function.
Figure 4: Opsinamides reversibly attenuate melanopsin-mediated photoresponses.

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Acknowledgements

We thank N. Boyle, B. Li, A. Pieris, R. Li, P. Rao, M. Cajina, H. Zhang (Lundbeck), H. Le, S. Keding (Salk Institute) for expert technical help. This work was supported by grants from the Hearst Foundation; US National Institutes of Health (NIH) grants NIH EY 016807, S10 RR027450 and NS066457 to S.P.; a Japan Society for the Promotion of Science fellowship to M.H.; Fyssen and Catharina foundation fellowships to L.S.M.; and NIH grant NIH EY017809 to P.J.S. and G.E.P.

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Author notes

  1. Kenneth A Jones, Megumi Hatori and Ludovic S Mure: These authors contributed equally to this work.

Authors and Affiliations

  1. Lundbeck Research USA Inc., Paramus, New Jersey, USA

    Kenneth A Jones, Roman Artymyshyn, Sang-Phyo Hong, Mohammad Marzabadi, Huailing Zhong & Jeffrey Sprouse

  2. Regulatory Biology Laboratory, Salk Institute for Biological Studies, North Torrey Pines Road, La Jolla, California, USA

    Megumi Hatori, Ludovic S Mure, Quansheng Zhu & Satchidananda Panda

  3. School of Veterinary Medicine and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska, USA

    Jayne R Bramley, Patricia J Sollars & Gary E Pickard

  4. Cyanaptic LLC, Stonington, Connecticut, USA

    Jeffrey Sprouse

  5. College of Optometry, The Ohio State University, Columbus, Ohio, USA

    Andrew T E Hartwick

  6. Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Gary E Pickard

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Contributions

K.A.J., M.H., L.S.M., J.R.B., R.A., S.-P.H., M.M., H.Z., Q.Z. and A.T.E.H. did the experiments. K.A.J., M.H., L.S.M., J.R.B., A.T.E.H., P.J.S., G.E.P., S.P. and J.S. analyzed the results and prepared figures. K.A.J., J.S., A.T.E.H., P.J.S., G.E.P. and S.P. designed experiments and prepared the manuscript.

Corresponding authors

Correspondence to Kenneth A Jones or Satchidananda Panda.

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Competing interests

K.J., R.A., S.-P.H., M.M., H.Z. and J.S. performed experimental work while they were employees of Lundbeck Research USA.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–10 and Supplementary Tables 1–4 (PDF 1588 kb)

Supplementary Movie 1

Negative phototaxis of wild-type neonatal (P8) mouse treated with vehicle. The first 2 min of the movie shows the pup's activity inside a plexiglass tube under complete darkness. The next 2 min shows the response to bright blue light illuminated from the left (shown as an arrow) of the plexiglass tube. The movie is sped up 4×. (MOV 19088 kb)

Supplementary Movie 2

Evaluation of negative phototaxis in a wild-type neonatal (P8) mouse treated with AA92593.The first 2 min of the movie shows the pup's activity inside a plexiglass tube under complete darkness. The next 2 min shows the response to bright blue light illuminated from the left (shown as an arrow) end of the plexiglass tube. The movie is sped up 4X. (MOV 20445 kb)

Supplementary Movie 3

Evaluation of negative phototaxis in neonatal (P8) Opn4–/– mouse. The first 2 min of the movie shows the pup's activity inside a plexiglass tube under complete darkness. The next 2 min shows the response to bright blue light illuminated from the left (shown as an arrow) end of the plexiglass tube. The movie is sped up 4×. (MOV 27461 kb)

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Jones, K., Hatori, M., Mure, L. et al. Small-molecule antagonists of melanopsin-mediated phototransduction. Nat Chem Biol 9, 630–635 (2013). https://doi.org/10.1038/nchembio.1333

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