Synthesis of delta9-Tetrahydrocannabinol Related Compounds

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，使人们关注大麻类化合物的化学和药理学。虽然这类化合物在化学和药理学方面取得了快速进展，但其产生各种中枢神经效应(CNS)的机制尚未建立。该合成计划的长期目标是开发A9-四氢大麻酚(THC)类似物，这将被证明是阐明大麻素作用机制的有用工具。 目前的重点是：(A)开发CB1选择性激动剂(B)开发大麻素CB1受体的变构调节剂(C)研究外周作用激动剂和拮抗剂(D)阐明配体-CB1受体迭代(E)开发结构上与THC相关的CB1中性拮抗剂/反向激动剂和(F)产生新的生物先导。所有这些目标都代表着当前计划的延续，该计划已经产生了几个值得注意的线索。 具体目标是(1)开发CB1选择性激动剂，(2)开发CB1受体的变构调节剂，(3)检测外周作用激动剂和拮抗剂，(4)阐明配体-CB1受体的相互作用，(5)开发结构上与THC相关的CB1中性/反向激动剂，以及(6)产生新的生物先导。 从这些类似物的合成和药理研究中获得的知识可能对研究结构活性关系(SAR)、耐受性、依赖性和开发治疗有用的药物至关重要，并将有助于更好地了解大麻类化合物的作用机制，并将有助于打击药物滥用问题。

DESCRIPTION (provided by applicant): The drug abuse problem in general and the wide spread use of marijuana in particular has focused attention on the chemistry and pharmacology of cannabinoids. Although rapid advances have been made in the chemistry and pharmacology of this class of compounds, the mechanisms involved in producing the various central nervous effects (CNS) have not been established. The long term goal of the synthetic program is to develop A9-tetrahydrocannabinol (THC) analogs which will prove to be useful tools in elucidating the mechanism of action of cannabinoids. The present emphasis will be directed towards: (a) development of CB1 selective agonists (b) development of allosteric modulators of the cannabinoid CB1 receptors (c) studying peripheral acting agonists and antagonists (d) elucidation of ligand-CB1 receptor iterations (e) development of CB1 neutral antagonist/inverse agonists which are structurally related to THC and (f) generation of new biological leads. All these goals represent a continuation of the current program which has generated several noteworthy leads. The specific aims are (1) development of CB1 selective agonists, (2) development of allosteric modulators of the CB1 receptors, (3) examining peripheral acting agonists and antagonists, (4) elucidation of ligand-CB1 receptor interactions, (5) development of CB1 neutral/inverse agonists which are structurally related to THC, and (6) generate new biological leads. The knowledge gained from the synthesis and pharmacological study of these analogs could be vital in the study of Structure Activity Relationships(SAR), tolerance, dependence and in the development of therapeutically useful drugs, and will lead to a better understanding of the mechanism of action of cannabinoids and will help combat the problem of drug abuse.