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):: A novel cannabinoid CB1/CB2 receptor partial agonist with antihyperalgesic and antiallodynic effects
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DOI：
10.1124/jpet.103.062836
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发表时间：
2004-08-01
影响因子：
3.5
通讯作者：
Mauler, F
中科院分区：
文献类型：
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作者：
De Vry, J;Denzer, D;Mauler, F
3-[2-氰基-3-（三氟甲基）苯基]-2-甲基-2-氧代-1H-吡唑（三氟甲基）苯氧基]苯基-4，4，4-三氟-1-丁磺酸酯（BAY 59-3074）是一种新型的选择性大麻素CB 1/CB 2受体配体（在大鼠和人大麻素CB 1和人CB 2受体处Ki分别= 55.4、48.3和45.5 nM），在鸟苷5-[γ（35）S]-硫代磷酸三乙基铵盐（[S-35] GTP γ S）结合试验中对这些受体具有部分激动剂性质。在大鼠中，BAY 59-3074对大麻素CB 1受体激动剂（-）-（R）-3-（2-羟甲基茚满基-4-氧基）苯基-4，4，4-三氟-1-丁磺酸酯（BAY 38-7271）在药物辨别程序中的作用，以及其在热板测定中的低温和镇痛作用，被大麻素CB 1受体拮抗剂N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺盐酸盐（SR 141716 A）阻断。BAY 593074（0.3 - 3 mg/kg，p.o.）在大鼠慢性神经病模型（慢性缩窄性损伤、备用神经损伤、胫神经损伤和脊神经结扎模型）和炎性疼痛模型（角叉菜胶和完全弗氏佐剂模型）中，对热或机械刺激诱导抗痛觉过敏和抗异常性疼痛作用。BAY 59-3074（lmg/kg，p.o.）在备用神经损伤模型中，在每天给药2周后维持。然而，对大麻素相关副作用的耐受性迅速发展（在5天内），其在高于lmg/kg的剂量下发生（例如，体温过低）。从1 mg/kg p.o.上调至32 mg/kg p.o.（每4天每日剂量加倍）预防了此类副作用的发生，而抗痛觉过敏和抗异常性疼痛功效得以维持/增加。每天口服1 - 10 mg/kg 14次后突然停药后未观察到戒断症状。可以得出结论，BAY 59-3074可以提供一种有价值的治疗方法来治疗各种慢性疼痛状况。
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.