3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074): a novel cannabinoid Cb1/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects.

Abstract

3-[2-Cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074) is a novel, selective cannabinoid CB(1)/CB(2) receptor ligand (K(i) = 55.4, 48.3, and 45.5 nM at rat and human cannabinoid CB(1) and human CB(2) receptors, respectively), with partial agonist properties at these receptors in guanosine 5-[gamma(35)S]-thiophosphate triethyl-ammonium salt ([(35)S]GTPgammaS) binding assays. In rats, generalization of BAY 59-3074 to the cue induced by the cannabinoid CB(1) receptor agonist (-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 38-7271) in a drug discrimination procedure, as well as its hypothermic and analgesic effects in a hot plate assay, were blocked by the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). BAY 59-3074 (0.3-3 mg/kg, p.o.) induced antihyperalgesic and antiallodynic effects against thermal or mechanical stimuli in rat models of chronic neuropathic (chronic constriction injury, spared nerve injury, tibial nerve injury, and spinal nerve ligation models) and inflammatory pain (carrageenan and complete Freund's adjuvant models). Antiallodynic efficacy of BAY 59-3074 (1 mg/kg, p.o.) in the spared nerve injury model was maintained after 2 weeks of daily administration. However, tolerance developed rapidly (within 5 days) for cannabinoid-related side effects, which occur at doses above 1 mg/kg (e.g., hypothermia). Uptitration from 1 to 32 mg/kg p.o. (doubling of daily dose every 4th day) prevented the occurrence of such side effects, whereas antihyperalgesic and antiallodynic efficacy was maintained/increased. No withdrawal symptoms were seen after abrupt withdrawal following 14 daily applications of 1 to 10 mg/kg p.o. It is concluded that BAY 59-3074 may offer a valuable therapeutic approach to treat diverse chronic pain conditions.

• Authors: Jean De Vry, Dirk Denzer, Elke Reissmueller, Maud Eijckenboom, Markus Heil, Heinrich Meier, Frank Mauler
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 310 Issue 2 Pg. 620-32 (Aug 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15140913 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluoro-1-butanesulfonate
• Alkanesulfonates
• Analgesics, Non-Narcotic
• Cannabinoids
• Nitriles
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2

Topics

• Alkanesulfonates (chemistry, pharmacology, therapeutic use)
• Analgesics, Non-Narcotic (chemistry, pharmacology, therapeutic use)
• Animals
• Cannabinoids (chemistry, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Humans
• Hyperalgesia (metabolism, prevention & control)
• Male
• Nitriles (chemistry, pharmacology, therapeutic use)
• Pain Measurement (drug effects, methods)
• Protein Binding (drug effects, physiology)
• Rats
• Receptor, Cannabinoid, CB1 (agonists, metabolism)
• Receptor, Cannabinoid, CB2 (agonists, metabolism)