Introduction of a triazole group in capsaicin-like compounds leads to the development of the first “hybrid” CB1 ligand and TRPV1 antagonist

Maria Grazia Cascio1, Sara Bacchiega2, Luciano De Petrocellis3, Alberto Minassi2, Giovanni Appendino2, Vincenzo Di Marzo1. 1Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Napoli, Italy, 2Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Novara, Italy, 3Endocannabinoid Research Group, Institute of Cibernetica, C.N.R., Pozzuoli, Napoli, Italy.

The amide linker of capsaicinoids is part of the pharmacophore requirements for transient receptor potential vanilloid type-1 (TRPV1) channel activation but is also a major site of metabolic lability, and its replacement with hydrolytically stable groups could improve the pharmacodynamic properties of these compounds (Appendino et al., 2002). The same holds true for the polyolefinic fatty acid chain in endogenous and synthetic cannabinoid CB1 receptor ligands (Reggio et al., 2002). In the present study we investigated the effect of the replacement of amide-and olefine bonds in a series of TRPV1 ligands of the capsaicinoid type by using a 1,2,3-triazole ring that is characterised by chemical stability and similarity with the amide bond. In particular, the vanilloid profile of the TRPV1 agonist nonivamide and the TRPV1 antagonist 6’-iodononivamide were compared with those of their corresponding triazole analogues, and a similar comparison was made between the unsaturated fatty acid vanillamides olvanil and phenylacetylrinvanil (PhAR) and their corresponding 1,2,3-triazole-bearing acyl vanillamides.

We found that most of the new compounds show good activity as ligands of the human recombinant TRPV1 receptor (6.1< pEC50<7.4) (by using HEK-293 transfected with human recombinant TRPV1 receptors, 50-100.000 cells/sample), although they are less potent than capsaicin (pEC50= 8.2±0.06), and generally unable to bind human recombinant CB1 and CB2 cannabinoid receptors (Ki>7 μM) (by using HEK-293 cells transfected with human CB1 or CB2 cannabinoid receptor, PerkinElmer, Italy). Interestingly, however, three triazole nonivamide analogues, Cav-84, -87 and -88, bind to CB1 receptors with moderate to weak affinity (Ki= 0.44, 4.0 and 2.7 μM respectively), but not to CB2 receptors. Furthermore, Cav-84, the 6’-iodo derivative of Cav-87, behaves also as a TRPV1 antagonist (pIC50= 6.5±0.07) slightly less potent than capsazepine (pIC50= 6.9±0.08), thus confirming our previous observations (Appendino et al., 2005) that 6’-iodination of the aromatic moiety of a capsaicinoid agonist (in this case Cav-87) can revert its activity at TRPV1 receptors. Thus, Cav-84 is the first example ever reported of a “hybrid” TRPV1 antagonist/CB1 ligand.

In conclusion, the results obtained in this study show that a triazole ring in capsaicinoid compounds, whilst still allowing a relatively good interaction with TRPV1 receptors, can behave as a surrogate group for the metabolically/chemically unstable amide and polyolefinic groups in fatty acid vanillamides also for their interaction with CB1 receptors. In view of its dual activity, Cav-84 represents a potential template for the development of new analgesic and anti-inflammatory compounds.

Appendino et al. (2002) J Med Chem, , 45:3739-45

Appendino et al. (2005) J Med Chem, 48:4663-9

Reggio et al. (2002) Prost Leukot Essent Fatty Acids, 66:143-60.