Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol.
Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol.
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发表时间：
1992-12
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通讯作者：
D. R. Compton;Lisa H. Gold;Susan J. Ward;R. Balster;Billy R. Martin
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作者：
D. R. Compton;Lisa H. Gold;Susan J. Ward;R. Balster;Billy R. Martin
在小鼠中评价了六种新型氨基烷基吲哚类似物，其结构与双重环氧合酶抑制剂和非阿片类镇痛剂普伐多林相关，以确定其药理学活性特征是否与δ 9-四氢大麻酚（δ 9-THC）所表现出的相似。类似物I（C2-H; C3-甲氧基-苯甲酰基）减少运动，但在高达21 mumol/kg时没有其他作用（体温降低、抗伤害感受或环不动性）。类似物II和III（C3-萘甲酰基;分别为C2-H和C2-甲基）具有Δ 9-THC所表现出的所有性质，ED 50值范围为0.68至18 μ mol/kg。类似物IV（C2-甲基; C3-蒽酰基）没有活性。立体选择性由以下事实证明：（+）-WIN-55，212（具有C2-H和C3-萘甲酰基取代基的半刚性衍生物的一种异构体）在所有试验中均具有中等效力（ED 50值范围为0.25-23 μ mol/kg），但（-）-WIN-55，212在高达57 μ mol/kg时无活性。活性氨基烷基吲哚化合物一般是最有效的低温生产。还评估了类似物在大鼠中产生δ 9-THC样辨别刺激效应的能力。对于该模型，Δ 9-THC作为辨别性刺激的ED 50为1.9 μ mol/kg。类似物II和III以及（+）-WIN-55，212产生Δ 9-THC样辨别效应，其ED 50值范围为0.33至4.3 μ mol/kg，而类似物I、IV和（-）-WIN-55，212则没有。尽管据报道在体外是大麻素受体拮抗剂，但类似物I、类似物IV和（-）-WIN-55，212（20 μ mol/kg）都不能拮抗小鼠或大鼠中δ 9-THC的体内药理学作用。（250字处删节）
Six novel aminoalkylindole analogs, related structurally to the dual cyclooxygenase inhibitor and nonopioid analgesic pravadoline, were evaluated in the mouse to determine whether their pharmacological profile of activity was similar to that exhibited by delta 9-tetrahydrocannabinol (delta 9-THC). Analog I (C2-H; C3-methoxy-benzoyl) reduced locomotion, but had no other effects (hypothermia, antinociception or ring-immobility) up to 21 mumol/kg. Analogs II and III (C3-naphthoyl; C2-H and C2-methyl, respectively) possessed all properties exhibited by delta 9-THC with ED50 values ranging from 0.68 to 18 mumol/kg. Analog IV (C2-methyl; C3-anthroyl) was devoid of activity. Stereoselectivity was demonstrated by the fact that (+)-WIN-55,212 (one isomer of a semirigid derivative possessing C2-H and C3-naphthoyl substituents) was moderately potent in all tests (ED50 values ranging from 0.25-23 mumol/kg), but (-)-WIN-55,212 was inactive up to 57 mumol/kg. Active aminoalkylindole compounds were generally least effective in the production of hypothermia. Analogs were also evaluated for their ability to produce delta 9-THC-like discriminative stimulus effects in rats. The ED50 for delta 9-THC as a discriminative stimuli for this model was 1.9 mumol/kg. Analog II and III and (+)-WIN-55,212 produced delta 9-THC-like discriminative effects with ED50 values ranging from 0.33 to 4.3 mumol/kg, whereas analogs I, IV and (-)-WIN-55,212 did not. Although reported to be cannabinoid receptor antagonists in vitro, neither analog I, analog IV nor (-)-WIN-55,212 (at 20 mumol/kg) antagonized the in vivo pharmacological effects of delta 9-THC in the mouse or rat.(ABSTRACT TRUNCATED AT 250 WORDS)