Compton D R, Prescott W R, Martin B R, Siegel C, Gordon P M, Razdan R K
Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
J Med Chem. 1991 Nov;34(11):3310-6. doi: 10.1021/jm00115a023.
The primary goal of this research was to synthesize a series of ether analogues of the cannabinoid drug class and to evaluate their agonist and antagonist pharmacological properties in either the mouse or the rat. Agonist and antagonist activity was evaluated in mice using a multiple-evaluation procedure (locomotor activity, tail-flick latency, hypothermia, ring immobility) and activity in rats determined in a discriminative stimulus paradigm. Additionally, novel analogues were evaluated for their ability to bind to the THC receptor site labeled by 3H-CP-55,940. None of the cannabinoid analogues were capable of attenuating the effects of delta 9-THC (3 mg/kg) in either the rat (doses up to 10 mg/kg) or in the mouse (doses up to 30 mg/kg). It also appears that the compounds with minimal in vivo activity are not mixed agonist/antagonists. These data would suggest that the phenolic hydroxyl is important for receptor recognition (binding) and in vivo potency. Additionally, cannabinoid methyl ethers previously considered inactive have been found to produce limited activity. Lastly, data suggest that delta 9,11-THC is more potent than previous reports indicated, and does possess pharmacological activity.
本研究的主要目标是合成一系列大麻素类药物的醚类似物，并在小鼠或大鼠中评估它们的激动剂和拮抗剂药理学特性。使用多评估程序（运动活性、甩尾潜伏期、体温过低、环形静止）在小鼠中评估激动剂和拮抗剂活性，并在辨别刺激范式中测定大鼠的活性。此外，评估新型类似物与用³H-CP-55,940标记的THC受体位点结合的能力。在大鼠（剂量高达10mg/kg）或小鼠（剂量高达30mg/kg）中，没有一种大麻素类似物能够减弱δ⁹-THC（3mg/kg）的作用。似乎体内活性最小的化合物不是混合激动剂/拮抗剂。这些数据表明酚羟基对于受体识别（结合）和体内效力很重要。此外，以前认为无活性的大麻素甲基醚已被发现具有有限的活性。最后，数据表明δ⁹,¹¹-THC比以前的报道更有效，并且确实具有药理活性。
