المؤلفون: Sortino, Rosalba, Cunquero, Marina, Castro‐Olvera, Gustavo, Gelabert, Ricard, Moreno, Miquel, Riefolo, Fabio, Matera, Carlo, Fernàndez‐Castillo, Noèlia, Agnetta, Luca, Decker, Michael, Lluch, José M., Hernando, Jordi, Loza‐Alvarez, Pablo, Gorostiza, Pau

المساهمون: R. Sortino, M. Cunquero, G. Castro‐olvera, R. Gelabert, M. Moreno, F. Riefolo, C. Matera, N. Fernàndez‐castillo, L. Agnetta, M. Decker, J.M. Lluch, J. Hernando, P. Loza‐alvarez, P. Gorostiza

مصطلحات موضوعية: Settore CHIM/08 - Chimica Farmaceutica, Settore BIO/14 - Farmacologia

الوصف: To interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two-photon photopharmacology and optogenetics. However, three-photon brain stimulation in vivo remains to be demonstrated. We report the regulation of neuronal activity in zebrafish larvae by three-photon excitation of a photoswitchable muscarinic agonist at 50 pM, a billion-fold lower concentration than used for uncaging, and with mid-infrared light of 1560 nm, the longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating brain activity in wild-type animals with spatiotemporal and pharmacological precision. Computational calculations predict that azobenzene-based ligands have high three-photon absorption cross-section and can be used directly with pulsed infrared light. The expansion of three-photon pharmacology will deeply impact basic neurobiology and neuromodulation phototherapies.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37823736; info:eu-repo/semantics/altIdentifier/wos/WOS:001104715800001; volume:135; issue:51; firstpage:1; lastpage:9; numberofpages:9; journal:ANGEWANDTE CHEMIE. INTERNATIONAL EDITION; https://hdl.handle.net/2434/1021271Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85177697549

الإتاحة: https://doi.org/10.1002/ange.202311181Test
https://hdl.handle.net/2434/1021271Test

المؤلفون: Sánchez-Sánchez, Jose Manuel, Riefolo, Fabio, Barbero-Castillo, Almudena, Sortino, Rosalba, Agnetta, Luca, Forcella, Marta, Bosch, Miquel, Decker, Michael, Gorostiza, Pau, Sanchez-Vives, Maria

المصدر: Brain Stimulation ; volume 16, issue 1, page 392-393 ; ISSN 1935-861X

مصطلحات موضوعية: Neurology (clinical), Biophysics, General Neuroscience

الإتاحة: https://doi.org/10.1016/j.brs.2023.01.789Test
https://api.elsevier.com/content/article/PII:S1935861X2300791X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1935861X2300791X?httpAccept=text/plainTest

المؤلفون: Prischich, Davia^1,2,3 (AUTHOR), Sortino, Rosalba^1,2 (AUTHOR), Gomila-Juaneda, Alexandre^1,2,4 (AUTHOR), Matera, Carlo^1,2,5 (AUTHOR), Guardiola, Salvador^6,7 (AUTHOR), Nepomuceno, Diane⁸ (AUTHOR), Varese, Monica^6,9 (AUTHOR), Bonaventure, Pascal⁸ (AUTHOR), de Lecea, Luis^10,11 (AUTHOR), Giralt, Ernest^6,12 (AUTHOR), Gorostiza, Pau^1,2,13 (AUTHOR) pau@icrea.cat

المصدر: Cellular & Molecular Life Sciences. 7/6/2024, Vol. 81 Issue 1, p1-15. 15p.

مصطلحات موضوعية: *OREXINS, *ENDOTHELIN receptors, *SLEEP, *PEPTIDES, *MOLECULAR dynamics, *NOCICEPTIN, *ISOMERS, *PHOTORECEPTORS

مستخلص: Orexinergic neurons are critically involved in regulating arousal, wakefulness, and appetite. Their dysfunction has been associated with sleeping disorders, and non-peptide drugs are currently being developed to treat insomnia and narcolepsy. Yet, no light-regulated agents are available to reversibly control their activity. To meet this need, a photoswitchable peptide analogue of the endogenous neuroexcitatory peptide orexin-B was designed, synthesized, and tested in vitro and in vivo. This compound – photorexin – is the first photo-reversible ligand reported for orexin receptors. It allows dynamic control of activity in vitro (including almost the same efficacy as orexin-B, high nanomolar potency, and subtype selectivity to human OX2 receptors) and in vivo in zebrafish larvae by direct application in water. Photorexin induces dose- and light-dependent changes in locomotion and a reduction in the successive induction reflex that is associated with sleep behavior. Molecular dynamics calculations indicate that trans and cis photorexin adopt similar bent conformations and that the only discriminant between their structures and activities is the positioning of the N-terminus. This, in the case of the more active trans isomer, points towards the OX2 N-terminus and extra-cellular loop 2, a region of the receptor known to be involved in ligand binding and recognition consistent with a "message-address" system. Thus, our approach could be extended to several important families of endogenous peptides, such as endothelins, nociceptin, and dynorphins among others, that bind to their cognate receptors through a similar mechanism: a "message" domain involved in receptor activation and signal transduction, and an "address" sequence for receptor occupation and improved binding affinity. [ABSTRACT FROM AUTHOR]

المؤلفون: Matera, Carlo, Calvé, Pablo, Casadó-Anguera, Verònica, Sortino, Rosalba, Gomila, Alexandre M J, Moreno, Estefanía, Gener, Thomas, Delgado-Sallent, Cristina, Nebot, Pau, Costazza, Davide, Conde-Berriozabal, Sara, Masana, Mercè, Hernando, Jordi, Casadó, Vicent, Puig, M Victoria, Gorostiza, Pau

المساهمون: C. Matera, P. Calvé, V. Casadó-Anguera, R. Sortino, A.M.J. Gomila, E. Moreno, T. Gener, C. Delgado-Sallent, P. Nebot, D. Costazza, S. Conde-Berriozabal, M. Masana, J. Hernando, V. Casadó, M.V. Puig, P. Gorostiza

مصطلحات موضوعية: GPCR, azobenzene, behavior, brainwave, dopamine, in vivo electrophysiology, optogenetic, optopharmacology, photochromism, photopharmacology, photoswitch, zebrafish, Settore CHIM/08 - Chimica Farmaceutica, Settore CHIM/06 - Chimica Organica, Settore BIO/14 - Farmacologia

الوصف: Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/36077512; info:eu-repo/semantics/altIdentifier/wos/WOS:000851120200001; volume:23; issue:17; firstpage:1; lastpage:18; numberofpages:18; journal:INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; http://hdl.handle.net/2434/937547Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85137562982; https://www.mdpi.com/1422-0067/23/17/10114Test

الإتاحة: https://doi.org/10.3390/ijms231710114Test
http://hdl.handle.net/2434/937547Test
https://www.mdpi.com/1422-0067/23/17/10114Test

المؤلفون: Sortino, Rosalba

المساهمون: Gorostiza Langa, Pablo Ignacio, Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Fotofarmacologia, Fotofarmacología, Photopharmacology, Fototeràpia, Fototerapia, Phototherapy, Radiació infraroja, Radiación infrarroja, Infrared radiation, Disseny de medicaments, Diseño de medicamentos, Drug design, Ciències de la Salut

الوقت: 615

الوصف: Tesi realitzada a l'Institut de Biotecnologia de Catalunya (IBEC) ; [eng] G protein-coupled receptors (GPCRs) modulate diverse cellular responses to the majority of neurotransmitters and hormones within the human body. They exhibit much structural and functional diversity and are responsive to a plethora of ligands and stimuli including both endogenous (e.g., biogenic amines, cations, lipids, peptides, and glycoproteins) and exogenous (e.g., therapeutic drugs, photons, tastants, and odorants). Due to the key roles of GPCRs in a myriad of physiological processes, signaling pathways associated with GPCRs are implicated in the pathophysiology of various diseases, ranging from metabolic, immunological, and neurodegenerative disorders to cancer and infectious diseases. Approximately 40% of clinically approved drugs mediate their effects by modulating GPCR signaling pathways, which makes them attractive targets for drug screening and discovery. In this work, we focus on distinct GPCRs which are involved in vital pathways, such as the muscarinic acetylcholine receptors, subtype -1 and subtype -2 (M1 and M2 mAChRs; class A); the dopamine receptor 1 (D1R; class A), and the metabotropic glutamate 6 receptor (mGlu6 receptor; class C). Both M1 receptor (M1R) and M2 receptor (M2R) are important drug targets for several diseases that affect the central nervous system (CNS), including Alzheimer's disease, Parkinson’s disease (PD), schizophrenia, sleep disorders, and acute brain diseases. M2R also represent a target for cardiac disfunctions; the D1R for hypertension and PD, and mGlu6 receptor for retinal degenerative diseases, like retinitis pigmentosa. Traditional pharmacological approaches for the modulation of the GPCRs activity are still limited since precise spatiotemporal control of a ligand is lost as soon it is administrated. Photopharmacology proposes the use of small diffusible molecules called photochromic ligands (PCLs) (or photoswitches) to overcome this shortfall, since their activity can be reversibly controlled ...

وصف الملف: 532 p.; application/pdf

العلاقة: http://hdl.handle.net/10803/690817Test

الإتاحة: http://hdl.handle.net/10803/690817Test

المؤلفون: Riefolo, Fabio, Sortino, Rosalba, Matera, Carlo, Claro Izaguirre, Enrique, Preda, Beatrice, Vitiello, Simone, Traserra, Sara, Jiménez, Marcel, Gorostiza Langa, Pablo Ignacio

المصدر: Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

مصطلحات موضوعية: Medicaments, Neurotransmissors, Fotoquímica, Drugs, Neurotransmitters, Photochemistry

الوصف: Tricyclic chemical structures are the core of many important drugs targeting all neurotransmitter pathways. These medicines enable effective therapies to treat from peptic ulcer disease to psychiatric disorders. However, when administered systemically, they cause serious adverse effects that limit their use. To obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimic the tricyclic chemical structure and display reversibly controlled activity. Pseudo-analogues of the tricyclic antagonist pirenzepine demonstrate that this is an effective strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both in vitro and in cardiac atria ex vivo. Despite the applied chemical modifications to make pirenzepine derivatives sensitive to light stimuli, the most potent candidate of the set, cryptozepine-2, maintained a moderate but promising M1 vs M2 subtype selectivity. These photoswitchable “crypto-azologs” of tricyclic drugs might open a general way to spatiotemporally target their therapeutic action while reducing their systemic toxicity and adverse effects.

وصف الملف: 63 p.; application/pdf

العلاقة: Versió postprint del document publicat a: https://doi.org/10.1021/acs.jmedchem.1c00504Test; Journal of Medicinal Chemistry, 2021, vol. 64, num.13, p. 9259-9270; https://doi.org/10.1021/acs.jmedchem.1c00504Test; http://hdl.handle.net/2445/178992Test

الإتاحة: https://doi.org/10.1021/acs.jmedchem.1c00504Test
http://hdl.handle.net/2445/178992Test

المؤلفون: Riefolo, Fabio, Matera, Carlo, Garrido Charles, Aida, Gomila Juaneda, Alexandre, Sortino, Rosalba, Agnetta, Luca, Claro Izaguirre, Enrique, Masgrau, Roser, Holzgrabe, Ulrike, Batlle, Montserrat, Decker, Michael, Guasch i Casany, Eduard, Gorostiza Langa, Pablo Ignacio

المصدر: Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

مصطلحات موضوعية: Calci, Ones electromagnètiques, Calcium, Electromagnetic waves

الوصف: Light-triggered reversible modulation of physiological functions offers the promise of enabling on-demand spatiotemporally controlled therapeutic interventions. Optogenetics has been successfully implemented in the heart, but significant barriers to its use in the clinic remain, such as the need for genetic transfection. Herein, we present a method to modulate cardiac function with light through a photoswitchable compound and without genetic manipulation. The molecule, named PAI, was designed by introduction of a photoswitch into the molecular structure of an M2 mAChR agonist. In vitro assays revealed that PAI enables light-dependent activation of M2 mAChRs. To validate the method, we show that PAI photoisomers display different cardiac effects in a mammalian animal model, and demonstrate reversible, real-time photocontrol of cardiac function in translucent wildtype tadpoles. PAI can also effectively activate M2 receptors using two-photon excitation with near-infrared light, which overcomes the scattering and low penetration of short-wave-length illumination, and offers new opportunities for intravital imaging and control of cardiac function.

وصف الملف: 9 p.; application/pdf

العلاقة: Versió postprint del document publicat a: https://doi.org/10.1021/jacs.9b03505Test; Journal of the American Chemical Society, 2019, vol. 141, num. 18, p. 7628-7636; https://doi.org/10.1021/jacs.9b03505Test; info:eu-repo/grantAgreement/EC/H2020/785907/EU//HBP_SGA2; http://hdl.handle.net/2445/147236Test

الإتاحة: https://doi.org/10.1021/jacs.9b03505Test
http://hdl.handle.net/2445/147236Test

المؤلفون: Sortino, Rosalba

المساهمون: Gorostiza Langa, Pablo Ignacio, Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació

المصدر: Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació

مصطلحات موضوعية: Fotofarmacologia, Fototeràpia, Radiació infraroja, Disseny de medicaments, Photopharmacology, Phototherapy, Infrared radiation, Drug design

الوصف: [eng] G protein-coupled receptors (GPCRs) modulate diverse cellular responses to the majority of neurotransmitters and hormones within the human body. They exhibit much structural and functional diversity and are responsive to a plethora of ligands and stimuli including both endogenous (e.g., biogenic amines, cations, lipids, peptides, and glycoproteins) and exogenous (e.g., therapeutic drugs, photons, tastants, and odorants). Due to the key roles of GPCRs in a myriad of physiological processes, signaling pathways associated with GPCRs are implicated in the pathophysiology of various diseases, ranging from metabolic, immunological, and neurodegenerative disorders to cancer and infectious diseases. Approximately 40% of clinically approved drugs mediate their effects by modulating GPCR signaling pathways, which makes them attractive targets for drug screening and discovery. In this work, we focus on distinct GPCRs which are involved in vital pathways, such as the muscarinic acetylcholine receptors, subtype -1 and subtype -2 (M1 and M2 mAChRs; class A); the dopamine receptor 1 (D1R; class A), and the metabotropic glutamate 6 receptor (mGlu6 receptor; class C). Both M1 receptor (M1R) and M2 receptor (M2R) are important drug targets for several diseases that affect the central nervous system (CNS), including Alzheimer's disease, Parkinson’s disease (PD), schizophrenia, sleep disorders, and acute brain diseases. M2R also represent a target for cardiac disfunctions; the D1R for hypertension and PD, and mGlu6 receptor for retinal degenerative diseases, like retinitis pigmentosa. Traditional pharmacological approaches for the modulation of the GPCRs activity are still limited since precise spatiotemporal control of a ligand is lost as soon it is administrated. Photopharmacology proposes the use of small diffusible molecules called photochromic ligands (PCLs) (or photoswitches) to overcome this shortfall, since their activity can be reversibly controlled by light with high precision. In this thesis, we combined ...

وصف الملف: 532 p.; application/pdf

العلاقة: http://hdl.handle.net/2445/210883Test; http://hdl.handle.net/10803/690817Test

الإتاحة: http://hdl.handle.net/2445/210883Test
http://hdl.handle.net/10803/690817Test

المؤلفون: Prischich, Davia, Sortino, Rosalba, Gomila-Juaneda, Alexandre, Matera, Carlo, Guardiola, Salvador, Nepomuceno, Diane, Varese, Monica, Bonaventure, Pascal, de Lecea, Luis, Giralt, Ernest, Gorostiza, Pau

الوصف: Orexinergic neurons are critically involved in regulating arousal, wakefulness, and appetite. Their dysfunction has been associated with sleeping disorders, and non-peptide drugs are currently being developed to treat insomnia and narcolepsy. Yet, no light-regulated agents are available to reversibly control their activity. To meet this need, a photoswitchable peptide analogue of the endogenous neuroexcitatory peptide orexin-B was designed, synthesized, and tested in vitro and in vivo. This compound (photorexin) is the first photo-reversible ligand reported for orexin receptors. It allows dynamic control of activity in vitro (including full agonism, nanomolar activity, and subtype selectivity to human OX2 receptors) and in vivo in zebrafish larvae by direct application in water. Photorexin induces dose- and light-dependent changes in locomotion and a reduction in the successive induction reflex that is associated with sleep behavior. Molecular dynamics calculations indicate that trans and cis photorexins adopt similar bent conformations and that the only discriminant between their structures and activities is the positioning of the N-terminus at the extracellular region of the orexin receptor. Thus, our approach could be extended to a broad and important family of neuropeptides that share a “message-address” mechanism when binding to their cognate receptors.

الإتاحة: https://doi.org/10.26434/chemrxiv-2023-r9kdsTest
https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/653ea3c2c573f893f16407e7/original/in-vivo-photocontrol-of-orexin-receptors-with-a-nanomolar-light-regulated-analogue-of-orexin-b.pdfTest

المؤلفون: Roque, Alicia, Sortino, Rosalba, Ventura, Salvador, Ponte, Inma, Suau, Pedro

المساهمون: Ministerio de Ciencia e Innovación, Institució Catalana de Recerca i Estudis Avançats

المصدر: Langmuir ; volume 31, issue 24, page 6782-6790 ; ISSN 0743-7463 1520-5827

الإتاحة: https://doi.org/10.1021/la504089gTest