Discovery of 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif

Journal of Medicinal Chemistry

Volumn 47, Issue 11, 2004, Pages 2939-2942

  Jagerovic, Nadine ^a   Hernandez Folgado, Laura ^a   Alkorta, Ibon ^a   Goya, Pilar ^a   Navarro, Miguel ^b   Serrano, Antonia ^c   Rodriguez De Fonseca, Fernando ^c   Dannert, M Teresa ^b   Alsasua, Angela ^b   Suardiaz, Margarita ^d   Pascual, David ^d   Martín, Maria Isabel ^d  

^a INSTITUTO DE QUÍMICA MÉDICA   (Spain)

^b UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^c HOSPITAL REGIONAL UNIVERSITARIO DE MÁLAGA   (Spain)

^d UNIVERSIDAD REY JUAN CARLOS   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 TRIAZOLE DERIVATIVE; 2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 5 (4 CHLOROPHENYL) 1 (2,4 DICHLOROPHENYL) 3 HEXYL 1H 1,2,4 TRIAZOLE; CANNABINOID RECEPTOR ANTAGONIST; RIMONABANT; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DETERMINATION; DRUG STRUCTURE; DRUG SYNTHESIS; GUINEA PIG; ILEUM; IN VIVO STUDY; MOUSE; NONHUMAN; RAT; STRUCTURE ANALYSIS; VAS DEFERENS;

ANIMALS; BEHAVIOR, ANIMAL; BINDING, COMPETITIVE; CEREBELLUM; GUINEA PIGS; ILEUM; MALE; MICE; MUSCLE CONTRACTION; MUSCLE, SMOOTH; RADIOLIGAND ASSAY; RATS; RECEPTORS, CANNABINOID; TRIAZOLES; VAS DEFERENS;

EID: 2442651556     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm031099y     Document Type: Article

References (22)

1. Pertwee, R. G. Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin. Invest. Drugs 2000, 9, 1553-1571.
2. Palmer, S. L.; Thakur, G. A.; Makriyannis, A. Cannabinergic ligands. Chem. Phys. Lipids 2002, 121, 3-19.
3. Wiley, J. L.; Martin, B. R. Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. Chem. Phys. Lipids 2002, 121, 57-63.
4. Goya, P.; Jagerovic, N. Recent advances in cannabinoid receptor agonists and antagonists. Expert Opin. Ther. Pat. 2000, 10, 1529-1538.
5. Goutopoulos, A.; Makriyannis, A. From cannabis to cannabinergics: new therapeutic opportunities. Pharmacol. Ther. 2002, 95, 103-117.
6. Jagerovic, N.; Goya, P.; Hernández-Folgado, L.; Alkorta, I.; Martín, M. I.; et al. 1,2,4-Triazole derivatives with cannabinoid properties. Patent WO03682833, 2003.
7. Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.; Calandra, B.; et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994, 350, 240-244.
8. Rinaldi-Carmona, M.; Barth, F.; Millan, J.; Derocq, J. M.; Casellas, P.; et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 1998, 284, 644-650.
9. Pertwee, R.; Griffin, G.; Fernando, S.; Li, X.; Hill, A.; et al. AM630, a competitive cannabinoid receptor antagonist. Life Sci. 1995, 56, 1949-1955.
10. Ooms, F.; Wouters, J.; Oscari, O.; Happaerts, T.; Bouchard, G.; et al. Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB(1) cannabinoid receptor ligands and potential antagonists: synthesis, lipophilicity, affinity, and molecular modeling. J. Med. Chem. 2002, 45, 1748-1756.
11. Czollner, L.; Szilágyi, G.; Langó, J.; Janáky, J. Synthesis of new 1,5-diphenyl-3-1H-1,2,4-triazoles substituted with H-, alkyl, or carboxyl groups at C-3. Arch. Pharm. (Weinheim, Ger.) 1990, 323, 225-227.
12. Pertwee, R. G.; Stevenson, L. A.; Elrick, D. B.; Mechoulam, R.; Corbett, A. D. Inhibitory effects of certain enantiomeric cannabinoids in the mouse vas deferens and the myenteric plexus preparation of guinea-pig small intestine. Br. J. Pharmacol. 1992, 105, 980-984.
13. Coutts, A. A.; Pertwee, R. G. Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus. Br. J. Pharmacol. 1997, 121, 1557-1566.
14. Pertwee, R. G.; Fernando, S. R.; Nash, J. E.; Coutts, A. A. Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. Br. J. Pharmacol. 1996, 118, 2199-2205.
15. Pertwee, R. G.; Griffin, G.; Lainton, J. A.; Huffman, J. W. Pharmacological characterization of three novel cannabinoid receptor agonists in the mouse isolated vas deferens. Eur. J. Pharmacol. 1995, 284, 241-247.
16. Griffin, G.; Fernando, S. R.; Ross, R. A.; McKay, N. G.; Ashford, M. L.; et al. Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur. J. Pharmacol. 1997, 339, 53-61.
17. Xu, L.; Izenwasser, S.; Katz, J. L.; Kopajtic, T.; Klein-Stevens, C.; et al. Synthesis and biological evaluation of 2-substituted 3β-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters. J. Med. Chem. 2002, 45, 1203-1210.
18. Lake, K. D.; Compton, D. R.; Varga, K.; Martin, B. R.; Kunos, G. Cannabinoid-Induced Hypotension and Bradycardia in Rats Is Mediated by CB1-Like Cannabinoid Receptors. J. Pharmacol. Exp. Ther. 1997, 281, 1030-1037.
19. Losonczy, A.; Biro, A. A.; Nusser, Z. Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. Proc. Natl. Acad Sci U.S.A. 2004, 101, 1362-1367.
20. Wade, S. M.; Lan, K.; Moore, D. J.; Neubig, R. R. Inverse agonist activity at the alpha(2A)-adrenergic receptor. Mol. Pharmacol. 2001, 59, 532-542.
21. Reggio, P. H. Pharmacophores for ligand recognition and activation/inactivation of the cannabinoid receptors. Curr. Pharm. Des. 2003, 9, 1607-1633.
22. Rosenqvist, E.; Ottersen, T. Crystal and Molecular-Structure of Delta-9-Tetrahydrocannabinolic Acid-B. Acta Chem. Scand., Ser. B 1975, 29, 379-384.