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

delta-9-THC 的分子位点和合成大麻素对脑功能的作用

• 批准号: 8933826
• 负责人: Carl R. Lupica
• 金额: $ 70.54万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8933826
• 关键词: Accident and Emergency department; Acute; Adverse effects; Affect; Agonist; Anxiety; Anxiety Disorders; Area; Behavior; Binding; Biological; Brain; CNR1 gene; Cannabinoids; Cannabis; Cardiovascular system; Caring; Chemicals; Cognition; Cognitive deficits; Collaborations; Dementia; Designer Drugs; Detection; Dose; Drug Formulations; Drug abuse; Drug usage; Emergency Situation; Epidemic; Exposure to; Floods; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Human; Human body; Illicit Drugs; Individual; Intramural Research Program; Knowledge; Laboratories; Lead; Learning; Marijuana; Marijuana Smoking; Marketing; Measures; Medical; Memory; Mental Depression; Mental disorders; Moods; Mus; National Institute of Drug Abuse; Nature; Neuraxis; Neurobiology; Neurologic; Neurons; Outcome; Pharmaceutical Preparations; Physiological; Plants; Population; Preclinical Drug Evaluation; Preparation; Presynaptic Terminals; Process; Property; Regulation; Relative (related person); Research; Safety; Site; Slice; Structure; Synapses; Synaptic Transmission; Testing; Tetrahydrocannabinol; Toxic effect; Transgenic Mice; Visit; analog; cannabinoid receptor; cognitive function; gamma-Aminobutyric Acid; molecular site; neurotransmitter release; psychologic; receptor; response; synthetic drug

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" 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 preliminary 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 acted 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.

在我们正在进行的研究中，以确定大麻素改变大脑功能的机制，我们已经开始与NIDA校内研究计划的设计师药物研究单位（DDRU）合作，比较“设计师”大麻素与传统“天然”大麻素的药理作用，如大麻植物中发现的δ-9-四氢大麻酚（δ-9-THC）。 设计师大麻素是一种精神活性分子，通常以“香”或其他植物相关制剂的形式销售。 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合成的，在大多数情况下，结构上类似于大麻素分子。 合成大麻素是批量生产的，并喷洒在植物材料上。 这些分子是在没有监管控制的非法实验室中制造的，这一事实往往导致暴露于可能导致意外毒性的掺杂物和污染物。 此外，这些合成大麻素的结构使得它们具有更强的作用，并且在由δ-9-THC激活的相同大麻素受体上具有更长的作用持续时间。 虽然这些药物中有许多被广泛使用，但其安全性通常未经测试，其完整的药理作用部位仍然未知。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世界范围内急诊室就诊的大量增加。 我们的初步研究已经检查了3种化合物，这些化合物是从美国缉毒局（DEA）缉获的材料中分离出来的，随后由专业化学家合成。 这些初步研究表明，化合物AM-2201和XLR-11是CB 1受体的完全激动剂，可抑制海马体中谷氨酸的释放。 这与δ-9-THC相反，δ-9-THC作为部分激动剂，表现出约一半的合成分子抑制谷氨酸反应的能力。 此外，这些合成大麻素在这方面比delta-9-THC更有效。 我们测试的另一种化合物，称为JWH-018，也比delta-9-THC更有效，但比其他2种合成化合物效力低。 到目前为止，我们的一般结论是，合成大麻素可以与大麻素CB 1受体结合，其效力和功效比δ-9-THC大得多。 我们预测，这将导致对神经递质释放的更大抑制，以及对大脑皮层依赖性认知的更大破坏，并可能导致人类更高水平的焦虑。 此外，与δ-9-THC相比，合成大麻素的这些药理学特性将导致更长的作用持续时间，因为其效力更高。