Cannabinergic Ligands & Drugs

描述（由申请人提供）：这是一个旨在通过合成已知大麻能位点的新型配体来确定大麻素活性的结构要求的项目的竞争性更新。当前资助期的目标包括CB 1和CB 2受体和大麻素酰胺酶作为我们结构活性相关性的靶点，并集中在三类大麻模拟配体，经典和非经典大麻素（CC，NCC）和大麻素（AN）。然而，这段时间见证了花生四烯酸转运蛋白（AT）和以2-花生四烯酸甘油（2AG）为代表的第二家族内源性配体的发现，以及作为一类新的CB 1和CB 2拮抗剂的二芳基吡唑（PY）类似物的开发。这些发展促使我们扩大了这个项目的范围，包括2AG和PY类似物的设计和合成，并增加了AT作为我们的结构活性相关性的目标。 我们的药物设计包括三个结构靶点; a）合成新的后一代CC和NCC，其包含构象受限的药效学特征和额外的杂原子; B）新的构象更明确的AN和2-AG类似物; c）新的吡唑类似物作为具有改进的药理学性质的后一代CB 1拮抗剂。我们将研究最成功的新型大麻能药物在溶液和膜中的立体电子性质，使用高分辨率NMR以及理论上使用分子力学和分子动力学。此外，还将在CB 1和CB 2受体的三维计算机模型上探索配体-受体相互作用的性质。将在膜制备物和整个动物中检测所有类似物对CB 1和CB 2的亲和力和功能特性（作为激动剂、拮抗剂和反向激动剂）。还将测试AEA和2AG类似物在抑制大麻素酰胺酶和大麻素转运蛋白中的有效性。该项目的长期治疗目标包括开发（a）尼古丁、类阿片、酒精或可卡因成瘾治疗剂;（B）不含大麻素已知精神作用的非类阿片镇痛剂。

DESCRIPTION (provided by applicant): This is a competing renewal for a project aimed at identifying the structural requirements for cannabinoid activity through the synthesis of novel ligands for the known cannabinergic sites. The goals of the current funding period included the CB1 and CB2 receptors and anandamide amidase as targets for our structure activity correlations and focused on three classes of cannabimimetic ligands, the classical and nonclassical cannabinoids (CCs, NCCs) and anandamide (AN). However, this intervening period has witnessed the discovery of the anandamide transporter (AT) and a second family of endogenous ligands represented by 2-arachidonyl glycerol (2AG) as well as the development of diarylpyrazole (PY) analogs as a new class of CB1 and CB2 antagonists. These developments have motivated us to widen the scope of this project by including the design and synthesis of 2AG and PY analogs and adding the AT as a target for our structure activity correlations. Our drug design encompasses three structural targets; a) the synthesis of novel later generation CCs and NCCs incorporating conformationally restricted pharmacophoric features and additional heteroatoms; b) novel conformationally more defined AN and 2-AG analogs; c) novel pyrazole analogs as later generation CB1 antagonists with improved pharmacological properties. We shall study the stereoelectronic properties of the most successful novel cannabinergic agents both in solution and in the membrane using high resolution NMR as well as theoretically using molecular mechanics and molecular dynamics. Furthermore, the nature of the ligand-receptor interaction will also be explored on three dimensional computer models of CB1 and CB2 receptors. All analogs will be tested for their affinities and functional properties (as agonists, antagonists, and inverse agonists) with regard to CB1 and CB2 in membrane preparations and in whole animals. The AEA and 2AG analogs will also be tested for their effectiveness in inhibiting anandamide amidase and the anandamide transporter. The long term therapeutic targets of the project include the development of (a) therapeutic agents for nicotine, opioid, alcohol or cocaine addiction; (b) non-opioid analgesics devoid of the known psychotropic properties of cannabinoids.