Modulators of the Endocannabinoid System

The areas of expertise of the research team broadly concern drug design, synthesis, and molecular recognition for the endocannabinoid system, a newly characterized biochemical system. This system which is related to the effects of Cannabis sativa, has emerged as a pharmacotherapeutic target due to its physiological significance. The contribution of the research group aims at understanding the molecular basis of cannabinoid activity and related biological targets for developing new therapeutic agents. The physiological processes involving most phytocannabinoids, endocannabinoids and synthetic cannabinoids are mediated by two G protein-coupled cannabinoid receptors (CBR), CB1R and CB2R. CB1R is predominantly and abundantly expressed in the central nervous system whereas CB2R is mainly found in the immune system. Off-target effects of cannabinoids have been a growing concern in the endocannabinoid field. Thus, two orphan G protein-coupled receptors, GPR55 and/or GPR18, have been proposed as putative cannabinoid receptors. Indirect modulation of the endocannabinoid system is also currently been explored, such as PPAR, AMPK cellular substrate or the enzymes involved in the kynurenine pathways.

Thus, the development of new pharmacological approaches to modulate this system offers the opportunity to focus on complex diseases, such as cardiovascular diseases, cancer, diabetes or neurodegenerative diseases, a group of pathologies described as chronic diseases. In addition, pharmacological tools are required to further characterize and understand this system.

This research requires a strong collaboration with national and international pharmacologists, biologists and computational scientists. In the last years, this research has been awarded several prizes [Honorific Mention Research Award of Esteve Foundation 2016; Finalist Lilly XXIII doctoral award (2015); Best Publication 2016 of SEIC; Award 2018 from RANF]. Besides, members of the group have a long-standing tradition of cooperating with the pharmaceutical industry. They are active in transferring knowledge through agreements with biotechnology companies and/or patents licensed for commercial exploitation.
The group keeps a strong involvement with scientific societies (e.g. EuChems, SEQT) and with scientific dissemination through organization of events and workshops.

RESEARCH LINES

New approaches to modulate the canonical cannabinoid receptors

Identification of new ligands for orphan G protein-coupled receptors

Indirect modulation of the endocannabinoid system (PPAR, AMPK, Kynurenine…)

Structural determinants for cannabinoid activity

SELECTED PUBLICATIONS AND PATENTS

Figuerola-Asencio L, Morales P, Zhao P, Hurst DP, Sayed SS, Colón, KL, Gómez-Cañas M, Fernández-Ruiz J, Croatt MP, Reggio PH, Abood ME, Jagerovic N. Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure−Activity Relationship. ACS Medicinal Chemistry Letters 2023; 14(1): 18-25. doi: 10.1021/acsmedchemlett.2c00325. PMID: 36655130. Q1

Morales P, Muller C, Jagerovic N, Reggio PH. Targeting CB2 and TRPV1: computational approaches for the identification of dual modulators. Frontiers in Molecular Biosciences 2022; 9: 841190. doi: 10.3389/fmolb.2022.841190. PMID: 3528126. Q2

Calvillo-Robledo A, Cervantes-Villagrana RD, Morales P, Marichal-Cancino B. The oncogenic lysophosphatidylinositol (LPI)/GPR55 signaling. Life Sciences 2022; 301(3): 120596. doi: 10.1016/j.lfs.2022.120596. PMID: 35500681. Q1

Franco R, Morales P, Navarro G, Jagerovic N, Reyes-Resina I. The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors. Frontiers in Pharmacology. 2022; 13: 852631. doi: 10.3389/fphar.2022.852631. PMID: 35250601. Q1

Vela M, García-Gimeno A, Sanchis A, Bono-Yagüe J, Cumella J, Lagartera L, Pérez C, Priego E.M, Campos A, Sanz P, Vázquez-Manrique R, Castro A. Neuroprotective effect of IND1316, an indole-based AMPK activator, in animal models of Huntington disease. ACS Chemical Neuroscience 2022; 13(2): 275-287. doi: 10.1021/acschemneuro.1c00758. PMID: 34962383. Q1

Sanz-Gómez M, Aledavood E, Beroiz-Salaverri M, Lagartera L, Vega-Martín E, Gil-Ortega M, Cumella J, Pérez C, Luque FJ, Estarellas C, Fernández-Alfonso MS, Castro. Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK-eNOS-NO pathway. Scientific Reports 2022; 12: 4225. doi: 10.1038/s41598-022-07077-8. PMID: 35273216. Q1

Sonia Burgaz; Concepción García; Claudia Gonzalo-Consuegra; Marta Gómez-Almería; Francisco Ruiz-Pino; Juan Diego Unciti; María Gómez-Cañas; Juan Alcalde; Paula Morales; Nadine Jagerovic; Carmen Rodríguez Cueto; Eva de Lago; Eduardo Muñoz; Javier Fernández-Ruiz. Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinsonʼs Disease and Amyotrophic Lateral Sclerosis. Molecules 2021; 26(24): 7643. doi: 10.3390/molecules26247643. PMID: 34946726. Q2

Tovar R, Gavito AL, Vargas A, Soverchia L, Hernandez-Folgado L, Jagerovic N, Baixeras E, Ciccocioppo R, Rodriguez de Fonseca F, Decara J. Palmitoleoylethanolamide is an efficient anti-obesity endogenous compound: comparison with Oleylethanolamide in Diet-Induced Obesity. Nutrients 2021; 13: 2589. doi: 10.3390/nu13082589. PMID: 34946726. Q1

Lago-Fernandez A, Zarzo-Arias S, Jagerovic N, Morales P. Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System. International Journal of Molecular Sciences 2021; 22: 1001. doi: 10.3390/ijms22031001. PMID: 33498245. Q1

Morales P, Jagerovic N. Synthetic and Natural Derivatives of Cannabidiol. Advances in Experimental Medicine and Biology 2021; 1297: 11-25. doi: 10.1007/978-3-030-61663-2_2. PMID: 33537934. Q2

Morales P, Navarro G, Gómez-Autet M, Fernandez-Ruiz J, Perez-Benito L, Cordomi A, Pardo L, Franco R, Jagerovic N. Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor. Chemistry – A European Journal 2020; 26(68):15839-15842. doi: 10.1002/chem.202003389. PMID: 32794211. Q1

Morales P, Lago-Fernandez A, Hurst DP, Sotudeh N, Brailoiu E, Reggio PH, Abood ME, Jagerovic N. Therapeutic Exploitation of GPR18: Beyond the Cannabinoids? Journal of Medicinal Chemistry 2020; 63:14216−14227. doi:10.1021/acs.jmedchem.0c00926. PMID: 3291497. D1

Morales P, Jagerovic N. Novel approaches and current challenges with targeting the endocannabinoid system. Expert Opinion in Drug Discovery 2020; 15: 917-930. doi:10.1080/17460441.2020.1752178. PMID: 32336154. Q1

Morales P, Jagerovic N. Antitumor Cannabinoid Chemotypes: Structural Insights. Frontiers in Pharmacology 2019; 10: 621. doi: 10.3389/fphar.2019.00621. PMID: 31214034. Q1

Franco R, Villa M, Morales P, Reyes-Resina I, Gutiérrez-Rodríguez A, Jiménez J, Jagerovic N, Martínez-Orgado J, Navarro G. Increased expression of cannabinoid CB2 and serotonin 5-HT1A heteroreceptor complexes in a model of newborn hypoxic-ischemic brain damage. Neuropharmacology 2019; 152: 58-66. doi: 10.1016/j.neuropharm.2019.02.004. PMID: 30738036. Q1

Aledavood E, Moraes G, Lameira J, Castro A, Luque FJ, Estarellas C. Understanding the Mechanism of Direct Activation of AMP-Kinase: Toward a Fine Allosteric Tuning of the Kinase Activity. Journal of Chemical Information and Modeling 2019; 59(6):2859-2870. doi: 10.1021/acs.jcim.8b00890. PMID: 30924649. Q1

Morales P, Goya P, Jagerovic N. Emerging strategies targeting CB2 cannabinoid receptor: Biased agonism and allosterism. Biochem Pharmacol. 2018; 157: 8-17. doi: 10.1016/j.bcp.2018.07.031. PMID: 30055149. Q1

Navarro G, Reyes-Resina I, Rivas-Santisteban R, Sánchez de Medina V, Morales P, Casano S, Ferreiro-Vera C, Lillo A, Aguinaga D, Jagerovic N, Nadal X, Franco R. Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes. Biochem Pharmacol. 2018; 157: 148-158. doi: 10.1016/j.bcp.2018.08.046. PMID: 30194918. Q1

Bort A, Quesada S, Ramos-Torres A, Gargantilla M, Priego EM, Raynal S, Lepifre F, Gasalla JM, Rodriguez-Henche N, Castro A, Díaz-Laviada I. Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation. Scientific Reports 2018, 8:4370. doi: 10.1038/s41598-018-22690-2. Q1

Lago-Fernandez A, Redondo V, Hernandez-Folgado L, Figuerola-Asencio L, Jagerovic N. New Methods for the Synthesis of Cannabidiol Derivatives. Methods Enzymol. 2017; 593:237-257. doi: 10.1016/bs.mie.2017.05.006. PMID: 28750806.

Morales P, Reggio PH, Jagerovic N. An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol. Front Pharmacol. 2017; 8: 422. doi: 10.3389/fphar.2017.00422. PMID: 28701957. Q1 top 5% most viewed and downloaded articles in the 2nd quarter of 2017

Ragusa G, Gómez-Cañas M, Morales P, Rodríguez-Cueto C, Pazos M, Asproni B, Cichero E, Fossa P, Pinna G, Jagerovic N, Fernández-Ruiz J, Murineddu G. New pyridazinone-4-carboxamides as new cannabinoid receptor type-2 inverse agonists: Synthesis, pharmacological data and molecular docking. Eur. J. Med. Chem. 2017, 127, 398-412. D1

Uranga JA, Cámara JC, Herradón E, Vera G, Jagerovic N, Quesada E, Fernández J, Lombó F, Abalo R. New Strategies For Treatment And Prevention Of Colorectal Cancer. Gastrointest. Cancers. 2017, 1, 193-170. A. Kumar Tyagi, S. Prasad (Eds.). Nova Science Publishers, Inc., New York, NY. ISBN: 978-1-53610-168-3

Morales, P.; Gómez-Cañas, M.; Navarro, G.; Hurst, D. P.; Carrillo-Salinas, F. J.; Lagartera, L.; Pazos, R.; Goya, P.; Reggio, P. H.; Guaza, C.; Franco, R.; Fernández-Ruiz, J.; Jagerovic, N. Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis. J.Med.Chem. 2016, 59, 6753–6771. D1

Morales, P.; Whyte, L. S.; Chicharro, R.; Gómez-Cañas, M.; Pazos, M. R.; Goya, P.; Irving, A. J.; Fernandez-Ruiz, J.; Ross, R. A.; Jagerovic, N. Identification of Novel GPR55 Modulators Using Cell-Impedance-Based Label-Free Technology. J.Med.Chem. 2016, 59, 1840–1853. D1

Gómez-Cañas, M.; Morales, P.; García-Toscano, L.; Navarrete, C.; Muñoz, E.; Jagerovic, N.; Fernández-Ruiz, J.; García-Arencibia, M.; Pazos, M. R. Biological Characterization of PM226, a Chromenoisoxazole, as a Selective CB2 Receptor Agonist with Neuroprotective Profile. Pharmacol.Res. 2016, 110, 205–215. Q1

P. Morales, P. Goya, N. Jagerovic, L. Hernandez-Folgado. Allosteric Modulators of the CB 1 Cannabinoid Receptor : A Structural Update Review. Cannabis Cannabinoid Res. 2016: 1 22-30. The fourth highest cited article of Cannabis and Cannabinoid Research (08/16/18).

P. Morales, L. Hernandez-Folgado, P. Goya, N. Jagerovic. Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update. Expert Opin. Ther. Pat. 2016: 26 843-856. Q1

P. Morales, N. Jagerovic. Advances towards the Discovery of GPR55 Ligands. Curr. Med. Chem. 2016: 23 2087-2100. Q1 (Medicinal Chemistry, accessed April 27, 2016)

Fonseca-Berzal, C.; Ibáñez-Escribano, A.; Reviriego, F.; Cumella, J.; Morales, P.; Jagerovic, N.; Nogal-Ruiz, J.J. ; Escario, J.A. ; da Silva, P.B. ; Soeiro, M. de N.C. ; Gómez-Barrio, A. ; Arán. V.J. Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles. Eur. J. Med. Chem. 2016: 115 295-310. D1

Castro Morera Ana, Sanz Bigorra Pascual, Vela Ruiz Marta, Garcia Gimeno María Adelaida. Derivatives of indol for the prevention and/or treatment of diabetes and related disorders. Patent: P201431364. Country ES. Priority date: 19.09.2014. Extended countries: WO 2016042194 A1. US 20170283378 A1. PCT/ES2015/070677. Entity: CSIC, CIBER

Morales, P.; Blasco-Benito, S.; Andradas, C.; Gómez-Cañas, M.; Flores, J.M.; Goya, P.; Fernández-Ruiz, J.; Sánchez, C.; Jagerovic, N. Selective, nontoxic CB2 cannabinoid o-quinone with in vivo activity against triple-negative breast cancer. J.Med.Chem. 2015, 58, 2256–2264. D1

N Jagerovic, P Morales Lazaro, R Ross, L Whyte. Selective modulators of the activity of the gpr55 receptor: chromenopyrazole derivatives. Patent Assignees: CSIC; University of Toronto. Patent: ESP201530608; PCT/ES2016/070314; WO2016/177922; EP3305794; CN107735397; AU2016257025; CA2985021; ES2593057; KR20180002717; BR112017023834; JP2018515499; US2018201620. Priority Date: 2015-05-05. Licensed to VivaCell Biotechnology dic2017

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