Photopharmacology – Reversible photoswitches
The MCS group has developed the first light-regulated mGluR5 negative allosteric modulators
The combination of a reversible photocontrolled ligand with illumination that is patterned in space and time can provide a novel degree of control and regulation of biological receptor activity. This method would allow controlling the location and the temporal extension of its activity. When applied in vivo, the use of reversible photoregulation could reduce side effects by targeting receptors located in specific tissues, establishing high precision, personalized drug schedules to patient needs.
In particular, azobenzene photoisomerization can be used to control biological functions. We have obtained diverse azobenzene molecules with light-dependent activity for GPCRs that can be used both in vitro and in vivo. Thus, local administration of a photoswitchable compound combined with localized illumination in the peripheral tissues of rodents or in the brain results in a precise illumination-dependent analgesic effect.
Among them we have obtained negative allosteric modulators (NAM) of metabotropic glutamate receptor subtype 5 (mGlu5) and azobenzene photoswitchable allosteric modulators of mGlu4 which allow the control of endogenous receptor activity with light and reversible inhibition of persistent pain symptoms by receptor photocontrol in the brain of freely behaving animals.
These compounds could be used to define novel and more precise therapeutic treatments and to study in vivo the physiological roles of the receptors.
Publications and patent applications
- Conformational diversity in class C GPCR positive allosteric modulation
Cannone G., Berto L., Malhaire F., Ferguson G., Fouillen A., Balor S., Font-Ingles J., Llebaria A., Goudet C., Kotecha A., Vinothkumar K.R., Lebon G.
Nature Communications 2025 Jan 13: 16: 619
- Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect
Josa-Culleré L., Aira Rodríguez C., Llebaria A.
Eur. J. Med. Chem. 2024 Dec 5: 279:116846 - A 'double-edged' role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs
Notartomaso S, Antenucci N, Mazzitelli M, Rovira X, Boccella S, Ricciardi F, Liberatore F, Gomez-Santacana X, Imbriglio T, Cannella M, Zussy C, Luongo L, Maione S, Goudet C, Battaglia G, Llebaria A, Nicoletti F, Neugebauer V.
Elife. 2024 Aug 22: 13:e94931
- Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity
Panarello S, González-Díez A, Berizzi A E, Malhaire F, Borràs-Tudurí R, Rovira X, Serra C, Prézeau L, Pin J P, Goudet C, Llebaria A, Gómez-Santacana X.
iSCIENCE. 2024 Jun 21: 27(6)110123
- Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration
Somalo-Barranco G, Pagano Zottola AC, Abdulrahman AO, El Zein RM, Cannich A, Muñoz L, Serra C, Oishi A, Marsicano G, Masri B, Bellocchio L, Llebaria A, Jockers R.
Cell Chem Biol. 2023 Aug 17;30(8):920-932.e7
- Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy
Josa-Culleré L, Llebaria A.
J Med Chem. 2023 Feb 9;66(3):1909-1927
- Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain
Pereira V, Arias JA, Llebaria A, Goudet C.
Pharmacol Res. 2023 Jan;187:106602
- Design and Validation of the First Family of Photo-Activatable Ligands for Melatonin Receptors
Somalo-Barranco G, Serra C, Lyons D, Piggins HD, Jockers R, Llebaria A.
J Med Chem. 2022 Aug 25;65(16):11229-11240.
- Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain
Notartomaso S, Antenucci N, Liberatore F, Mascio G, Boccadamo Pompili SV, Font J, Scioli M, Luongo L, Arcella A, Gradini R, Llebaria A, Nicoletti F.
Int J Mol Sci. 2022 Jul 20;23(14):8018
- Photoswitchable allosteric modulators for metabotropic glutamate receptors
Gómez-Santacana X, Panarello S, Rovira X, Llebaria A.
Curr Opin Pharmacol. 2022 Oct;66:102266
- Ligand Targeting the β1-Adrenoceptor Enables Light-Control of the Cardiac Rhythm
Duran-Corbera A, Faria M, Ma Y, Prats E, Dias A, Catena J, Martinez KL, Raldua D, Llebaria A, Rovira X.
Angew Chem Int Ed Engl. 2022 Jul 25;61(30):e202203449
- Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea
Garrido-Charles A, Huet A, Matera C, Thirumalai A, Hernando J, Llebaria A, Moser T, Gorostiza P.
J Am Chem Soc. 2022 Jun 1;144(21):9229-9239
- Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations
Nasrallah C, Cannone G, Briot J, Rottier K, Berizzi AE, Huang CY, Quast RB, Hoh F, Banères JL, Malhaire F, Berto L, Dumazer A, Font-Ingles J, Gómez- Santacana X, Catena J, Kniazeff J, Goudet C, Llebaria A, Pin JP, Vinothkumar KR, Lebon G
Cell Rep. 2021 Aug 31;36(9):109648
- Mechanistic Insights into Light-Driven Allosteric Control of GPCR Biological Activity
Ricart-Ortega M, Berizzi AE, Pereira V, Malhaire F, Catena J, Font J, Gómez-
Santacana X, Muñoz L, Zussy C, Serra C, Rovira X, Goudet C, Llebaria AACS Pharmacol Transl Sci. 2020 Aug 18;3(5):883-895
- Photoswitchable Antagonists for a Precise Spatiotemporal Control of β2-Adrenoceptors
Duran-Corbera A, Catena J, Otero-Viñas M, Llebaria A, Rovira X.
J Med Chem. 2020 Aug 13;63(15):8458-8470
- Development and validation of a mass spectrometry binding assay for mGlu5 receptor
Ricart-Ortega M, Berizzi AE, Catena J, Malhaire F, Muñoz L, Serra C, Lebon G, Goudet C, Llebaria A.
Anal Bioanal Chem. 2020 Sep;412(22):5525-5535
- Reversible silencing of endogenous receptors in intact brain tissue using 2-photon pharmacology
Pittolo S, Lee H, Lladó A, Tosi S, Bosch M, Bardia L, Gómez-Santacana X, Llebaria A, Soriano E, Colombelli J, Poskanzer KE, Perea G, Gorostiza P
Proc. Natl. Acad. Sci. U. S. A., 2019, 116 (27), 13680-13689 - GPCR photopharmacology
Ricart-Ortega M, Font J, Llebaria A
Mol. Cell. Endocrinol., 2019, 488, 36-51 - A light-controlled allosteric modulator unveils a role for mGlu4 receptors during early stages of ischemia in the rodent cerebellar cortex
Bossi S, Helleringer R, Galante M, Monlleó E, Trapero A, Rovira X, Daniel H, Llebaria A, McLean H
Front. Cell. Neurosci., 2018, 12, 449 - Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4
Zussy C, Gómez-Santacana X, Rovira X, de Bundel D, Ferrazzo S, Bosch D, Asede D, Malhaire F, Acher F, Giraldo J, Valjent E, Ehrlich I, Ferraguti F, Pin JP, Llebaria A, Goudet C
Mol. Psychiatr., 2018, 23(3), 509-520 - Optical activation of endogenous metabotropic glutamate receptor 4 (mGlu4) in the amygdala dynamically regulates symptoms associated with persistent inflammatory pain
Zussy C, Gómez-Santacana X, Rovira X, de Bundel D, Ferrazzo S, Bosch D, Asede D, Malhaire F, Acher F, Giraldo J, Valjent E, Ehrlich I, Ferraguti F, Pin JP, Llebaria A, Goudet C
Mol. Psychiatr., 2018, 23(3), 489 - Shedding light on metabotropic glutamate receptors using optogenetics and photopharmacology
Goudet C, Rovira X, Llebaria A
Curr. Opin. Pharmacol., 2018, 38, 8-15 - Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer
Liu J, Zhang Z, Moreno-Delgado D, Dalton JA, Rovira X, Trapero A, Goudet C, Llebaria A, Giraldo J, Yuan Q, Rondard P, Huang S, Liu J, Pin JP
eLife, 2017, 6, e26985 - Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu5 negative allosteric modulation
Gómez-Santacana X, Dalton JAR, Rovira X, Pin JP, Goudet C, Gorostiza P, Giraldo J, Llebaria A
Eur. J. Med. Chem., 2017, 127, 567-576 - Illuminating phenylazopyridines to photoswitch metabotropic glutamate receptors: from the flask to the animals
Gómez-Santacana X, Pittolo S, Rovira X, Lopez M, Zussy C, Dalton JAR, Faucherre A, Jopling C, Pin JP, Ciruela F, Goudet C, Giraldo J, Gorostiza P, Llebaria A
ACS Central Sci., 2017, 3(1), 81-91 - OptoGluNAM4.1, a photoswitchable allosteric antagonist for real-time control of mGlu4 receptor activity
Rovira X, Trapero A, Pittolo S, Zussy C, Faucherre A, Jopling C, Giraldo J, Pin JP, Gorostiza P, Goudet C, Llebaria A
Cell Chem. Biol., 2016, 23(8), 929-934 - Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches
Izquierdo-Serra M, Bautista-Barrufet A, Trapero A, Garrido-Charles A, Diaz-Tahoces A, Camarero N, Pittolo S, Valbuena S, Perez-Jimenez A, Gay M, Garcia-Moll A, Rodriguez-Escrich C, Lerma J, De La Villa P, Fernandez E, Pericas MA, Llebaria A, Gorostiza P
Nat. Commun., 2016, 7, 12221 - Shining light on an mGlu5 photoswitchable NAM: a theoretical perspective
Dalton JAR, Lans I, Rovira X, Malhaire F, Gómez-Santacana X, Pittolo S, Gorostiza P, Llebaria A, Goudet C, Pin JP, Giraldo J
Curr. Neuropharmacol., 2016, 14(5), 441-454 - WO2015044358 Glutamate receptor photomodulators
Consejo Superior de Investigaciones Científicas (CSIC), Universitat Autónoma de Barcelona, Fundació Institut de Bioenginyeria de Catalunya (IBEC), Centre National de la Recherche Scientifique (CNRS), Fundació Institució Catalana de Recerca i Estudis Avançats (ICREA)
- Exploring the active conformation of cyclohexane carboxylate positive allosteric modulators of the type 4 metabotropic glutamate receptor
Rovira X, Harrak Y, Trapero A, González-Bulnes P, Malhaire F, Pin JP, Goudet C, Giraldo J, Llebaria A
ChemMedChem, 2014, 9(12), 2685-2698 - An allosteric modulator to control endogenous G protein-coupled receptors with light
Pittolo S, Gómez-Santacana X, Eckelt K, Rovira X, Dalton J, Goudet C, Pin JP, Llobet A, Giraldo J, Llebaria A, Gorostiza P
Nat. Chem. Biol., 2014, 10(10), 813-815 - A double effect molecular switch leads to a novel potent negative allosteric modulator of metabotropic glutamate receptor 5
Gómez-Santacana X, Rovira X, Dalton JA, Goudet C, Pin JP, Gorostiza P, Giraldo J, Llebaria A
MedChemComm, 2014, 5(10), 1548-1554 - Computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (in)activation
Dalton JAR, Gómez-Santacana X, Llebaria A, Giraldo J
J. Chem Inf. Model., 2014, 54(5), 1476-1487