First “hybrid” ligands of vanilloid TRPV1 and cannabinoid CB₂ receptors and non-polyunsaturated fatty acid-derived CB₂-selective ligands

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• 作者：Giovanni Appendino ; Maria Grazia Cascio ; Sara Bacchiega ; Aniello Schiano Moriello ; Alberto Minassi ; Adè ; le Thomas ; Ruth Ross ; Roger Pertwee ; Luciano De Petrocellis and Vincenzo Di Marzo
• 关键词：Endocannabinoid ; Vanilloid ; Inflammation ; Receptor ; Channel ; Anandamide
• 刊名：FEBS Letters
• 出版年：2006
• 出版时间：23 January 2006
• 年：2006
• 卷：580
• 期：2
• 页码：568-574
• 全文大小：156 K

文摘

12-Phenylacetyl-ricinoleoyl-vanillamide (phenylacetylrinvanil, PhAR, IDN5890), is an ultra-potent agonist of human vanilloid TRPV1 receptors also endowed with moderate affinity for human cannabinoid CB₂ receptors. To improve its CB₂ affinity and temper its potency at TRPV1, the modification of the polar headgroup and the lipophilic 12-acylgroup of PhAR was pursued. Replacement of the vanillyl headgroup of PhAR with various aromatic or alkyl amino groups decreased activity at TRPV1 receptors, although the dopamine, cyclopropylamine, 1′-(R)- and 1′-(S)-methyl-ethanolamine, and ethanolamine derivatives retained significant potency (EC₅₀ 31–126 nM). Within these compounds, the 12-phenylacetylricinoleyl cyclopropylamide and ethanolamide were the strongest ligands at CB₂ receptors, with K_i of 22 and 44 nM, and 14- and >20-fold selectivity over cannabinoid CB₁ receptors, respectively. The propyl- and allyl-derivatives also exhibited high affinity at CB₂ receptors (K_i = 40 and 22 nM, with 40 and >80-fold selectivity over CB₁ receptors, respectively), but no activity at TRPV1 receptors. The cyclopropyl- and allyl-derivatives behaved as CB₂ inverse agonists in the GTP-γ-S binding assay. Addition of para-methoxy, -tert-butyl or -chlorine groups to the 12-phenylacetyl moiety of PhAR produced compounds that retained full potency at TRPV1 receptors, but with improved selectivity over CB₂ or CB₁ receptors. Thus, the manipulation of PhAR led to the development of the first CB₂/TRPV1 dual ligands and of an entirely new class of inverse agonists at CB₂ receptors. Both types of compounds might find application in the treatment of inflammation, and represent new molecular probes to investigate the endocannabinoid–endovanilloid signalling system.