Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, 116 Mugar Hall, 360 Huntington Ave, Boston, MA 02115, USA.
Psychopharmacology (Berl). 2012 Mar;220(2):417-26. doi: 10.1007/s00213-011-2491-1. Epub 2011 Oct 12.
The endocannabinoid signaling system (ECS) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies. Current focus is on chemical modifications of the hexahydrocannabinol (HHC) nabilone (Cesamet(®)).
To characterize the novel, high-affinity cannabinoid receptor 1 (CB(1)R) HHC-ligand AM2389 [9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays.
CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251, a CB(1)R-selective antagonist/inverse agonist. Additionally, two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 (0.18 and 0.56 mg/kg) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1% saccharin/water. Generalization/substitution tests were conducted with AM2389, AM5983, and Δ(9)-tetrahydrocannabinol (Δ(9)-THC).
Δ(9)-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 (0.1 and 0.3 mg/kg). AM251 (3 and 10 mg/kg) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389. In drug discrimination, the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025, 0.0571, and 0.2635 mg/kg, respectively, in the low-dose condition. The corresponding ED(50) values in the high-dose condition were 0.0069, 0.1246, and 0.8438 mg/kg, respectively. Onset of the effects of AM2389 was slow with a protracted time-course; the functional, perceptual in vivo half-life was approximately 17 h.
This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course. The AM2389 chemotype appears well suited for further drug development, and AM2389 currently is used to probe behavioral consequences of sustained ECS activation.
内源性大麻素信号系统（ECS）已成为开发新型治疗药物的目标，因为 ECS 功能障碍与各种病理有关。目前的重点是对六氢大麻酚（HHC）纳比隆（Cesamet（®））进行化学修饰。
用 AM251（一种 CB1R 选择性拮抗剂/反向激动剂）在两种啮齿动物临床前测定中，对新型高亲和力大麻素受体 1（CB1R）HHC 配体 AM2389 [9β-羟基-3-（1-己基-环丁-1-基）-六氢大麻酚]进行表征。
用 AM251 评估 AM2389 诱导的小鼠体温降低的 CB1R 介导作用，AM251 是一种 CB1R 选择性拮抗剂/反向激动剂。此外，两组大鼠在以 0.1%蔗糖水为动力的双选择操作性条件反射任务中，20 分钟后从载体中区分出全大麻素氨基烷基吲哚 AM5983（0.18 和 0.56mg/kg）。用 AM2389、AM5983 和 Δ（9）-四氢大麻酚（Δ（9）-THC）进行了概括/替代测试。
与 AM2389（0.1 和 0.3mg/kg）相比，Δ（9）-THC（30mg/kg）诱导的体温降低具有更快的发作和更短的作用持续时间。AM251（3 和 10mg/kg）减弱/阻断了 0.3mg/kg AM2389 诱导的体温降低。在药物辨别中，效力顺序为 AM2389>AM5983>Δ（9）-THC，低剂量条件下的 ED50 值分别为 0.0025、0.0571 和 0.2635mg/kg，高剂量条件下的 ED50 值分别为 0.0069、0.1246 和 0.8438mg/kg。AM2389 作用的开始缓慢，作用持续时间较长；功能、体内感知半衰期约为 17 小时。
这种有效的大麻素 HHC 表现出缓慢的作用开始和延长的作用时间。AM2389 化学型似乎非常适合进一步的药物开发，目前 AM2389 用于研究持续 ECS 激活的行为后果。
