Bass Caroline E, Griffin Graeme, Grier Mark, Mahadevan Anu, Razdan Raj K, Martin Billy R
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Smith Building, 410 North 12th Street, Richmond, VA 23227, USA.
Pharmacol Biochem Behav. 2002 Dec;74(1):31-40. doi: 10.1016/s0091-3057(02)00945-0.
The central cannabinoid receptor (CB(1)) antagonist, SR-141716A, has been used extensively to ascertain that cannabinoids interact with the CB(1) receptor. SR-141716A has been shown to produce effects opposite of cannabinoids when administered alone. It has been theorized that SR-141716A may act as an inverse agonist at the CB(1) receptor or by disinhibiting an endogenous cannabinoid tone. In an effort to ascertain the exact interaction between SR-141716A and the CB(1) receptor, we have conducted a structure-activity relationship study to compare CB(1) receptor affinity of SR-141716A analogs with their ability to produce an increase in locomotor activity. SR-141716A produced a significant increase in locomotor activity in mice within the first hour of administration. Twenty SR-141716A analogs from five different chemical series were also tested. Our data implicate particular regions of the SR-141716A molecule that may be involved in stimulation and depression of locomotor activity. When the K(I) of the analogs was plotted against the percent stimulation that each analog produced, it is evident that there is no correlation between the ability of the analogs to stimulate locomotor activity and their affinity for the CB(1) receptor. [35S]GTPgammaS binding data indicate that SR-141716A and five of the analogs are inverse agonists. However, none of the analogs demonstrating inverse agonism produce stimulation of locomotor activity. It is therefore concluded that the SR-141716A-induced stimulation in locomotor activity is not the result of inverse agonist activity at the CB(1) receptor or by disinhibition of an endogenous tone.
中枢大麻素受体（CB(1)）拮抗剂SR-141716A已被广泛用于确定大麻素与CB(1)受体的相互作用。单独给药时，SR-141716A已被证明会产生与大麻素相反的效果。理论上认为，SR-141716A可能作为CB(1)受体的反向激动剂，或通过解除内源性大麻素张力的抑制作用来发挥作用。为了确定SR-141716A与CB(1)受体之间的确切相互作用，我们进行了一项构效关系研究，以比较SR-141716A类似物的CB(1)受体亲和力与其产生运动活性增加的能力。SR-141716A在给药后的第一小时内使小鼠的运动活性显著增加。还测试了来自五个不同化学系列的20种SR-141716A类似物。我们的数据表明，SR-141716A分子的特定区域可能与运动活性的刺激和抑制有关。当将类似物的K(I)与每个类似物产生的刺激百分比进行绘图时，很明显，类似物刺激运动活性的能力与其对CB(1)受体的亲和力之间没有相关性。[35S]GTPγS结合数据表明，SR-141716A和其中五种类似物是反向激动剂。然而，没有一种表现出反向激动作用的类似物能刺激运动活性。因此得出结论，SR-141716A诱导的运动活性刺激不是CB(1)受体反向激动剂活性的结果，也不是内源性张力解除抑制的结果。
