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                            Library & Multimedia
 The Spicy Story of Cannabimimetic Indoles
NCJ Number
              303994

Author(s)
          Allyn C. Howlett;
                        Brian F. Thomas;
                        John W. Huffman
Date Published

2021
Annotation
              The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever; however, as the drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain.
Abstract
              Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket, but that WIN55212-2 primarily used steric interactions via aromatic stacking; whereas, cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines. (publisher abstract modified)
      
  
          Additional Details
Grant Number(s)
        2012-R2-CX-K001


  
  
        
  Agencies
        NIJ-Sponsored


  
  
        
  Publication Type
        Research (Applied/Empirical)


  
  
        
  Award
        Characterization of Designer Drugs: Chemical Stability, Exposure, and Metabolite Identification
    
  
  
Date Published: January 1, 2021
    
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