> Details

Burstein, Ethan S; Ott, Thomas R; Bulow, Anne; Ek, Fredrick; Ma, Jian‐Nong; Pettersson, Hanna; Jensen, Jacob; Ottesen, Lars; Owens, Michelle L; Clemons, Bryan; Bertozzi, Fabio; Johnson, Robert W; Sweetnam, Timothy; Currier, Erika; Del Tredici, Andria L; Schiffer, Hans H; Piu, Fabrice; McFarland, Krista; Tabatabaei, Ali; Gardell, Luis R; Olsson, Roger; Bonhaus, Doug

Identification of novel antagonists of CB1 cannabinoid receptors

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: Identification of novel antagonists of CB1 cannabinoid receptors
  • Contributor: Burstein, Ethan S; Ott, Thomas R; Bulow, Anne; Ek, Fredrick; Ma, Jian‐Nong; Pettersson, Hanna; Jensen, Jacob; Ottesen, Lars; Owens, Michelle L; Clemons, Bryan; Bertozzi, Fabio; Johnson, Robert W; Sweetnam, Timothy; Currier, Erika; Del Tredici, Andria L; Schiffer, Hans H; Piu, Fabrice; McFarland, Krista; Tabatabaei, Ali; Gardell, Luis R; Olsson, Roger; Bonhaus, Doug
  • imprint: Wiley, 2008
  • Published in: The FASEB Journal
  • Language: English
  • DOI: 10.1096/fasebj.22.1_supplement.1127.14
  • ISSN: 1530-6860; 0892-6638
  • Keywords: Genetics ; Molecular Biology ; Biochemistry ; Biotechnology
  • Origination:
  • Footnote:
  • Description: <jats:p>CB1 cannabinoid receptor antagonists have therapeutic utility in CNS as well as metabolic disorders. We identified multiple novel structural classes of CB1 antagonists and characterized a compound called AC‐462 in detail. AC‐462 is structurally distinct from rimonabant and other biarylpyrazoles, utilizing a dibenzothiazepine structure as its scaffold. The binding Ki's of AC‐462 to human and rat CB1 receptors are 0.2 and 2 nM, respectively. AC‐462 is highly selective for CB1 receptors over CB2, and over 60 other GPCRs, transporters and ion channels. AC‐462 has pro‐cognitive actions in radial arm maze and novel object recognition paradigms and augments apomorphine‐induced rotations in the 6‐hydroxy dopamine lesion model of Parkinson's disease. AC‐462 reverses CP 55,940 induced analgesia and hypothermia in mice, and is orally active as an appetite suppressant, reducing food intake in fasted Sprague‐Dawley rats. Once daily dosing of AC‐462 to Zucker rats over 14‐days significantly decreased body weight compared to vehicle‐treated animals. A large number of analogs of AC‐462 with similar <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> activities were produced. One of these analogs called AC‐999 produced robust decreases in body weight of diet‐induced obese (DIO) mice dosed orally qd over 14‐days. These results demonstrate that AC‐462 and its analogs have therapeutic potential for a wide array of indications.</jats:p>