Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin‐like activity

FEBS Letters

Di Marzo, Vincenzo¹  De Petrocellis, Luciano⁴  Davis, John B²  Pertwee, Roger G³  Bisogno, Tiziana¹ 

[1] Endocannabinoid Research Group, Istituto per la Chimica di Molecole di Interesse Biologico, C.N.R., Via Toiano 6, 80072, Arco Felice, Napoli, Italy;Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK;Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK;Endocannabinoid Research Group, Istituto di Cibernetica, C.N.R., Via Toiano 6, 80072, Arco Felice, Napoli, Italy

关键词: Capsaicin;    Vanilloid;    Anandamide;    Cannabinoid;    Calcium;    Transporter;    AEA;    arachidonoylethanolamide;    AMT;    anandamide membrane transporter;    FAAH;    fatty acid amide hydrolase;    HEK;    human embryonic kidney;    N-AVAM;    N-acyl-vanillyl-amine;    hVR1;    human vanilloid receptor type 1;   

DOI  :  10.1016/S0014-5793(00)02082-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Some synthetic agonists of the VR1 vanilloid (capsaicin) receptor also inhibit the facilitated transport into cells of the endogenous cannabinoid anandamide (arachidonoylethanolamide, AEA). Here we tested several AEA derivatives containing various derivatized phenyl groups or different alkyl chains as either inhibitors of the AEA membrane transporter (AMT) in intact cells or functional agonists of the VR1 vanilloid receptor in HEK cells transfected with the human VR1. We found that four known AMT inhibitors, AM404, arvanil, olvanil and linvanil, activate VR1 receptors at concentrations 400–10 000-fold lower than those necessary to inhibit the AMT. However, we also found three novel AEA derivatives, named VDM11, VDM12 and VDM13, which inhibit the AMT as potently as AM404 but exhibit little or no agonist activity at hVR1. These compounds are weak inhibitors of AEA enzymatic hydrolysis and poor CB₁/CB₂ receptor ligands. We show for the first time that, despite the overlap between the chemical moieties of AMT inhibitors and VR1 agonists, selective inhibitors of AEA uptake that do not activate VR1 (e.g. VDM11) can be developed.

【 授权许可】

Unknown