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

3-[2-Cyano-3-(trifluoromethyl) phenoxy] phenyl-4,4,4-trifluoro-1-butanesulfonate ( BAY 59-3074) is a novel, selective cannabinoid CB1/CB2 receptor ligand (K-i = 55.4, 48.3, and 45.5 nM at rat and human cannabinoid CB1 and human CB2 receptors, respectively), with partial agonist properties at these receptors in guanosine 5-[gamma(35)S]-thiophosphate triethyl-ammonium salt ([S-35] GTPgammaS) binding assays. In rats, generalization of BAY 59-3074 to the cue induced by the cannabinoid CB1 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 593074 (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.