3-[2-Cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074): A Novel Cannabinoid CB₁/CB₂Receptor 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 ϭ 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- [␥ 35 S]-thiophosphate triethyl-ammonium salt ([ 35 S]GTP␥S) binding assays. In rats, generalization of BAY 59-3074 to the cue induced by the cannabinoid CB 1 receptor agonist (Ϫ)-(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.

Fatty Acid Amide Hydrolase (FAAH) Inhibitors Exert Pharmacological Effects, but Lack Antinociceptive Efficacy in Rats with Neuropathic Spinal Cord Injury Pain

“…The current study confirms previous findings in neuropathic pain models of a lack tolerance to the antinociceptive effect following repeated treatment with a CB receptor agonist [20], [35], [36]. By contrast, a loss of efficacy following repeated treatment with morphine in SCI rats has been observed [20].…”

Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55

“…Partial CB 1 and CB 2 receptor agonists had been shown to reduce inflammationassociated hyperalgesia and to possess antiallodynic effects in animal models. 31,32 Thus, magnolol and its metabolites may have the same in vivo effects due to their action on CB receptors.…”

Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy

“…[14-16] The cannabinoids have been shown to be effective in a number of animal models of neuropathic pain including diabetic neuropathy [17, 18] and chronic nerve constriction. [19, 20] Although 4 recent studies on the effect of inhaled cannabis on neuropathic pain have been promising, none have focused specifically on painful DPN. [21-24]…”