Molecular sites of delta-9-THC and synthetic cannabinoid actions on brain function

在我们正在进行的确定大麻素改变大脑功能的机制的研究中，我们已经开始与NIDA内部研究计划的设计者药物研究单位(DDRU)合作，比较“设计者”大麻素和在大麻植物中发现的传统“天然”大麻素的药理作用，如β-9-四氢大麻酚(Delta-9-THC)。特制大麻素是一种精神活性分子，通常被宣传为“香”、“香料”或其他与植物有关的配方。这些药物的精神活性成分通常是由业余化学家在秘密实验室中合成的，在大多数情况下结构类似于大麻素分子。合成的大麻素是散装制成的，然后喷洒在植物材料上。这些分子是在没有管制的非法实验室中制造的，这一事实往往导致接触到掺杂物和污染物，从而可能导致意外的毒性。此外，这些合成大麻素的结构是这样的，它们具有更强的作用，并且对由Delta-9-THC激活的相同的大麻素受体具有更长的作用持续时间。尽管其中许多药物被广泛使用，但它们的安全性通常未经测试，其完整的药理作用部位仍不清楚。这些化合物的非法性质及其不完全了解的药理作用导致使用这些药物的个人在全世界范围内的急诊室就诊人数大幅增加。 我们的初步研究检查了3种化合物，这些化合物是从美国缉毒局(DEA)查获的材料中分离出来的，随后由专业化学家合成。这些研究表明，化合物AM-2201和XLR-11是CB1受体的完全激动剂，可以抑制海马区谷氨酸的释放。这与Delta-9-THC相反，Delta-9-THC据称起到部分激动剂的作用，显示出大约一半作为合成分子抑制谷氨酸反应的能力。此外，在这方面，这些合成大麻素比Delta-9-THC有效得多。我们测试的另一种化合物JWH-018也比Delta-9-THC有效，但不如其他两种合成化合物有效。到目前为止，我们的总体结论是，合成的大麻素可以与大麻素CB1受体结合，比Delta-9-THC具有更大的效力和效率。我们预测，这将导致神经递质释放的更大抑制，以及对海马体依赖的认知的更大破坏，并可能导致人类更高水平的焦虑。此外，与Delta-9-THC相比，合成大麻素的这些药理特性将导致更长的作用时间，因为它们具有更高的效力。正在进行的研究旨在寻找这些化合物对大脑中非大麻受体靶点的“异地”影响。目前，我们正在评估这些配体与大脑皮层中的5-羟色胺1型受体以及大鼠脑片伏核中钙激活的钾通道的潜在相互作用。初步数据表明，这些合成的大麻素可能在中枢神经系统的其他分子位置起作用。

In our ongoing studies to identify the mechanisms through which cannabinoids alter brain function, we have begun collaborating with the Designer Drug Research Unit (DDRU) at the NIDA Intramural Research Program, to compare the pharmacological effects of "designer" cannabinoids with those of conventional "natural" cannabinoids such at delta-9-tetrahydrocannabinol (delta-9-THC), found in the marijuana plant. Designer cannabinoids are psychoactive molecules that are often marketed as "incense", "spice" or other plant-related formulations. The psychoactive components of these drugs are typically synthesized in clandestine laboratories by amateur chemists, and in most cases structurally resemble cannabinoid molecules. The synthetic cannabinoids are made in bulk and sprayed onto plant material. The fact that these molecules are made in illicit laboratories without regulatory control often leads to exposure to adulterants and contaminants that can result in unintended toxicity. In addition, the structure of these synthetic cannabinoids is such that they have stronger effects, and longer durations of action at the same cannabinoid receptors that are activated by delta-9-THC. Although many of these drugs are widely consumed, their safety is generally untested, and their complete pharmacological sites of action remain unknown. The illicit nature of these compounds and their incompletely understood pharmacological actions has resulted in a large increase in world-wide emergency room visits by individuals using these drugs. Our initial studies have examined 3 compounds that were isolated from material seized by the U.S. Drug Enforcement Agency (DEA), and subsequently synthesized by professional chemists. These studies show that the compounds AM-2201, and XLR-11 are full agonists at CB1 receptors that inhibit glutamate release in the hippocampus. This is in contrast to delta-9-THC, which purportedly acts as a partial agonist, demonstrating approximately one-half of the ability to inhibit glutamate responses as the synthetic molecules. In addition, these synthetic cannabinoids were much more potent than delta-9-THC on this measure. Another compound that we tested, known as JWH-018, was also more efficacious than delta-9-THC, but less potent than the other 2 synthetic compounds. Our general conclusion thus far is that the synthetic cannabinoids can bind to the cannabinoid CB1 receptor with much greater potency and efficacy than delta-9-THC. We predict that this will lead to a much greater inhibition of neurotransmitter release, and a greater disruption of hippocampus-dependent cognition, and perhaps result in much higher levels of anxiety in humans. Additionally, these pharmacological properties of the synthetic cannabinoids would result in much longer durations of action, compared to delta-9-THC, because of the higher potency. Ongoing studies are designed to look for "off site" effects of these compounds at non-cannabinoid receptor targets in the brain. Currently, we are evaluating potential interactions of these ligands with serotonin type 1 receptors in the cerebral cortex, as well as at calcium-activated potassium channels in the nucleus accumbens in rat brain slices. Preliminary data suggest that there may be actions of these synthetic cannabinoids at other molecular sites in the CNS.