Anandamide -- Structure/Activity Relationships

说明(申请人提供)：总体上的药物滥用问题，特别是大麻的广泛使用，使人们对大麻的化学和药理学产生了关注。自发现大麻素受体以来的十年里，在大麻素领域取得了很大的进展。现已证实，大麻素受体至少有两种：CB1受体和CB2受体，CB1受体存在于中枢神经系统内外，CB2受体主要存在于外周。目前已经发现了两种主要的内源性配体，花烷胺(AEA)和2-花生四烯基甘油(2-Ara-G1)。也被称为内源性大麻素，它们同时存在于中枢和外周组织中。该计划的长期目标是开发AEA的结构活性关系(SAR)，这些AEA是二十烷类化合物，与其他大麻类化合物没有化学/结构关系。我们认为，AEA的SAR对于了解AEA和其他大麻素如何与同一受体相互作用至关重要。我们的具体目标是：(1)继续研究AEA的花生四烯酸部分的SAR；(2)开发AEA/THC(四氢大麻酚)杂化化合物；(3)开发新型的ANT膜转运蛋白(AMT)探针；(4)合成作为AEA潜在代谢物的羟基化AEA类似物。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系列中更有效的激动剂、部分激动剂和拮抗剂。这可能导致发现一种带有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，揭示参与脑功能的机制，并导致在炎症、疼痛、血管扩张、抗肿瘤治疗和其他中枢神经系统相关疾病领域的治疗药物的开发。这项拟议的研究将增加我们对这类重要化合物的药理作用的了解，从而为医疗保健领域发现新的药物。

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.