2. Academic Validation
  3. Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

  • J Med Chem. 2016 Jul 28;59(14):6753-6771. doi: 10.1021/acs.jmedchem.6b00397.
Paula Morales 1,  María Gómez-Cañas # 2 3,  Gemma Navarro # 4,  Dow P Hurst 5,  Francisco J Carrillo-Salinas 6,  Laura Lagartera 1,  Ruth Pazos 2 3,  Pilar Goya 1,  Patricia H Reggio 5,  Carmen Guaza 6,  Rafael Franco 4,  Javier Fernández-Ruiz 2 3,  Nadine Jagerovic 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica, Consejo Superior de Investigaciones Científicas, Calle Juan de la Cierva, 3, E-28006 Madrid, Spain.
  • 2 Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
  • 3 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), E-28040 Madrid, Spain.
  • 4 Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad de Barcelona, E-08028 Barcelona, Spain.
  • 5 Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, North Carolina 27402, United States.
  • 6 Grupo de Neuroinmunología Neurobiología Funcional y de Sistemas, Instituto Cajal, Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain.
  • # Contributed equally.
PMID: 27309150 DOI: 10.1021/acs.jmedchem.6b00397
Abstract

A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among Others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 Agonist isoxazole derivative, was tested in the acute phase of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.

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