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The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies.

Abstract

Two cannabinoids receptors have been characterised in mammals; cannabinoid receptor type 1 (CBI) which is ubiquitous in the central nervous system (CNS), and cannabinoid receptor type 2 (CBII) that is expressed mainly in immune cells. Cannabinoids have been used in the treatment of nausea and emesis, anorexia and cachexia, tremor and pain associated with multiple sclerosis. These treatments are limited by the psychoactive side-effects of CBI activation. Recently CBII has been described within the CNS, both in microglia and neuronal progenitor cells (NPCs), but with few exceptions, not by neurons within the CNS. This has suggested that CBII agonists could have potential to treat various conditions without psycho-activity. This article reviews the potential for CBII agonists as treatments for neurological conditions, with a focus on microglia and NPCs as drug targets. We first discuss the role of microglia in the healthy brain, and then the role of microglia in chronic neuroinflammatory disorders, including Alzheimer's disease and Parkinson's disease, as well as in neuroinflammation following acute brain injury such as stroke and global hypoxia. As activation of CBII receptor on microglia results in suppression of the proliferation and activation of microglia, there is potential for the anti-inflammatory properties of CBII agonist to treat neuropathologies that involve heightened microglia activity. In addition, activating CBII receptors may result in an increase in proliferation and affect migration of NPCs. Therefore, it is possible that CBII agonists may assist in the treatment of neuropathologies by increasing neurogenesis. In the second part of the article, we review the state of development of CBII selective drugs with an emphasis on critical aspects of CBII agonist structural activity relationship (SAR).

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology & Toxicology, University of Otago, Dunedin, New Zealand.

    Source

    MeSH

    Animals
    Cannabinoids
    Central Nervous System
    Computer Simulation
    Depression
    Down Syndrome
    Humans
    Inflammation
    Microglia
    Molecular Structure
    Neurodegenerative Diseases
    Neurogenesis
    Receptor, Cannabinoid, CB2

    Pub Type(s)

    Journal Article
    Review

    Language

    eng

    PubMed ID

    20236042

    Citation

    TY - JOUR T1 - The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies. AU - Rivers,Jack Rocky-Jay, AU - Ashton,John Clive, PY - 2010/3/19/entrez PY - 2010/3/20/pubmed PY - 2010/6/9/medline SP - 47 EP - 64 JF - Central nervous system agents in medicinal chemistry JO - Cent Nerv Syst Agents Med Chem VL - 10 IS - 1 N2 - Two cannabinoids receptors have been characterised in mammals; cannabinoid receptor type 1 (CBI) which is ubiquitous in the central nervous system (CNS), and cannabinoid receptor type 2 (CBII) that is expressed mainly in immune cells. Cannabinoids have been used in the treatment of nausea and emesis, anorexia and cachexia, tremor and pain associated with multiple sclerosis. These treatments are limited by the psychoactive side-effects of CBI activation. Recently CBII has been described within the CNS, both in microglia and neuronal progenitor cells (NPCs), but with few exceptions, not by neurons within the CNS. This has suggested that CBII agonists could have potential to treat various conditions without psycho-activity. This article reviews the potential for CBII agonists as treatments for neurological conditions, with a focus on microglia and NPCs as drug targets. We first discuss the role of microglia in the healthy brain, and then the role of microglia in chronic neuroinflammatory disorders, including Alzheimer's disease and Parkinson's disease, as well as in neuroinflammation following acute brain injury such as stroke and global hypoxia. As activation of CBII receptor on microglia results in suppression of the proliferation and activation of microglia, there is potential for the anti-inflammatory properties of CBII agonist to treat neuropathologies that involve heightened microglia activity. In addition, activating CBII receptors may result in an increase in proliferation and affect migration of NPCs. Therefore, it is possible that CBII agonists may assist in the treatment of neuropathologies by increasing neurogenesis. In the second part of the article, we review the state of development of CBII selective drugs with an emphasis on critical aspects of CBII agonist structural activity relationship (SAR). SN - 1875-6166 UR - https://www.unboundmedicine.com/medline/citation/20236042/abstract/The_development_of_cannabinoid_CBII_receptor_agonists_for_the_treatment_of_central_neuropathies_ L2 - http://www.eurekaselect.com/85808/article ER -