Anandamide -- Structure/Activity Relationships

Anandamide——结构/活性关系

• 批准号: 7027088
• 负责人: RAJ RAZDAN
• 金额: $ 20.02万
• 依托单位: ORGANIX, INC.
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027088
• 关键词: Cannabis; amidases; analog; anandamide; arachidonate; cannabinoid receptor; cannabinoids; chemical structure function; chemical synthesis; drug abuse; enzyme inhibitors; ethanolamines; ligands; membrane transport proteins

DESCRIPTION (provided by applicant): The drug abuse problem in general and the widespread use of marijuana, in particular, have focused attention on the chemistry and pharmacology of the plant Cannabis Sativa. In the decade since the discovery of the cannabinoid receptors, much progress has been made in the cannabinoid field. It has been established that there are at least two types of cannabinoid receptors; CB1 receptors which are present both inside and outside the central nervous system (CNS) and CB2 receptors which are found mainly in the periphery. Two main endogenous ligands have been discovered, anandamide (AEA) and 2-arachidonylglycerol (2-Ara-G1). Also known as endocannabinoids, they are both present in central as well as peripheral tissues. The long term goal of this program is to develop Structure Activity Relationships (SAR) of AEA which are eicosanoids, and bear no chemical/structural relationship to other cannabinoids. We feel that SAR of AEA will be critical for understanding how AEA and other cannabinoids interact with the same receptor. Our specific aims are (i) to continue to examine the SAR of arachidonic acid portion of AEA (ii) to develop AEA/THC (tetrahydrocannabinol) hybrids (iii) to develop novel anandamide membrane transporter (AMT) probes and (iv) to synthesize hydroxylated AEA analogs as potential metabolites of AEA. The synthesis of these analogs and their subsequent biological evaluation will provide us with more potent agonists, partial agonists and antagonists in the AEA series. This may result in the discovery of a silent antagonist with an AEA template and could lead to the discovery of other cannabinoid subtype receptors, reveal mechanisms involved in brain function, and lead to the development of therapeutic drugs in the areas of inflammation, pain, vasodilation, antitumor therapy and other CNS related diseases. The proposed study will increase our understanding of the pharmacological action of this important class of compounds, leading to the discovery of new drugs for the health care field.

描述（由申请人提供）： 一般的药物滥用问题，特别是大麻的广泛使用，使人们注意到大麻植物的化学和药理学。自大麻素受体发现以来的十年中，大麻素领域取得了很大进展。已经确定存在至少两种类型的大麻素受体;存在于中枢神经系统（CNS）内部和外部的CB 1受体和主要在外周中发现的CB 2受体。已发现两种主要的内源性配体，花生四烯酸酰胺（AEA）和2-花生四烯酸甘油（2-Ara-G1）。也被称为内源性大麻素，它们都存在于中央和外周组织中。该计划的长期目标是开发AEA的结构活性关系（SAR），AEA是类花生酸，与其他大麻素没有化学/结构关系。我们认为AEA的SAR对于理解AEA和其他大麻素如何与相同受体相互作用至关重要。我们的具体目标是（i）继续研究AEA的花生四烯酸部分的SAR（ii）开发AEA/THC（四氢大麻酚）杂交（iii）开发新的大麻素膜转运蛋白（AMT）探针和（iv）合成羟基化AEA类似物作为AEA的潜在代谢产物。这些类似物的合成及其后续的生物学评价将为我们提供AEA系列中更强效的激动剂、部分激动剂和拮抗剂。这可能导致发现具有AEA模板的沉默拮抗剂，并可能导致发现其他大麻素亚型受体，揭示涉及脑功能的机制，并导致开发炎症、疼痛、血管舒张、抗肿瘤治疗和其他CNS相关疾病领域的治疗药物。拟议的研究将增加我们对这类重要化合物的药理作用的理解，从而发现用于医疗保健领域的新药。