Thomas Brian F, Zhang Yanan, Brackeen Marcus, Page Kevin M, Mascarella S Wayne, Seltzman Herbert H
Research Triangle Institute, Research Triangle Park, NC 27709-2194, USA.
AAPS J. 2006 Oct 27;8(4):E665-71. doi: 10.1208/aapsj080476.
Interest in cannabinoid pharmacology increased dramatically upon the identification of the first cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are discovered. Using CB1 receptor (CB1R) systems, medicinal chemistry programs began screening libraries searching for cannabinoid ligands, ultimately leading to the discovery of the first potent cannabinoid receptor antagonist, SR141716A (Rimonabant). Its demonstrated efficacy in treating obesity and facilitating smoking cessation, among other impressive pharmacological activities, has furthered the interest in cannabinoid receptor antagonists as therapeutics, such that the number of patents and publications covering this class of compounds continues to grow at an impressive rate. At this time, medicinal chemistry approaches including combinatorial chemistry, conformational constraint, and scaffold hopping are continuing to generate a large number of cannabinoid antagonists. These molecules provide an opportunity to gain insight into the 3-dimensional structure-activity relationships that appear crucial for CB1R-ligand interaction. In particular, studies in which conformational constraints have been imposed on the various pyrazole ring substituents of SR141716A provide a direct opportunity to characterize changes in conformation/conformational freedom within a single class of compounds. While relatively few conformationally constrained molecules have been synthesized to date, the structure-activity information is often more readily interpreted than in studies where entire substituents are replaced. Thus, it is the focus of this mini-review to examine the structural properties of SR141716A, and to use conformationally constrained molecules to illustrate the importance of conformation and conformational freedom to CB1R affinity, selectivity, and efficacy.
1998年首个大麻素受体（CB1）被鉴定出来后，对大麻素药理学的兴趣急剧增加，并且随着更多内源性大麻素和大麻素受体的发现，这种兴趣还在持续扩大。利用CB1受体（CB1R）系统，药物化学项目开始筛选文库以寻找大麻素配体，最终导致了首个强效大麻素受体拮抗剂SR141716A（利莫那班）的发现。它在治疗肥胖症和促进戒烟方面所展示出的疗效，以及其他令人印象深刻的药理活性，进一步激发了人们对大麻素受体拮抗剂作为治疗药物的兴趣，以至于涵盖这类化合物的专利和出版物数量继续以惊人的速度增长。目前，包括组合化学、构象限制和骨架跃迁在内的药物化学方法继续产生大量的大麻素拮抗剂。这些分子为深入了解对CB1R - 配体相互作用似乎至关重要的三维构效关系提供了机会。特别是，对SR141716A的各种吡唑环取代基施加构象限制的研究，提供了一个直接的机会来表征单一类化合物内构象/构象自由度的变化。虽然迄今为止合成的构象受限分子相对较少，但与整个取代基被替换的研究相比，构效信息往往更容易解读。因此，本综述的重点是研究SR141716A的结构特性，并利用构象受限分子来说明构象和构象自由度对CB1R亲和力、选择性和效力的重要性。
