Palmer S L, Khanolkar A D, Makriyannis A
Departments of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Curr Pharm Des. 2000 Sep;6(13):1381-97. doi: 10.2174/1381612003399419.
During the past several years, cannabinoid biology has witnessed marked advances that has propelled it to the forefront of biomedical research. These new developments have also provided an opportunity to examine the physiological and biochemical events underlying the use and abuse of cannabis as well as elucidating the biological role of the endogenous cannabinoid ligands (endocannabinoids). The biological targets for endocannabinoids include the cannabinoid receptors (CB1 and CB2), the enzyme anandamide amidohydrolase (AAH), and the carrier protein referred to as the anandamide transporter (ANT). The identification of arachidonylethanolamide (anandamide, AEA) as an endogenous cannabinoid has been an important development in cannabinoid research which has led to the identification of two proteins associated with cannabinoid physiology in addition to the CB1 and CB2 receptors. These proteins are anandamide amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and the anandamide transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane. Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective agents possessing somewhat different pharmacological properties than the cannabinoids. A number of such analogs have now been reported many of which possess markedly improved cannabinoid receptor affinities and metabolic stabilities compared to those of the parent ligand. Generally, anandamide and all known analogs exhibit significant selectivities with high affinities for the CB1 receptor and modest to very low affinity for the CB2 receptor. In a relatively short period of time, pharmacological and biochemical studies have confirmed initial speculations that anandamide is either a neuromodulator or neurotransmitter and has significantly advanced our understanding of cannabinoid biochemistry. This summary seeks to define the pharmacology of endocannabinoids and to focus on the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor.
在过去几年中，大麻素生物学取得了显著进展，使其跃居生物医学研究的前沿。这些新进展也为研究大麻使用和滥用背后的生理和生化事件以及阐明内源性大麻素配体（内源性大麻素）的生物学作用提供了契机。内源性大麻素的生物学靶点包括大麻素受体（CB1和CB2）、酶花生四烯酸乙醇胺水解酶（AAH）以及被称为花生四烯酸乙醇胺转运体（ANT）的载体蛋白。花生四烯酸乙醇胺（阿南达米德，AEA）作为一种内源性大麻素的鉴定是大麻素研究中的一项重要进展，除了CB1和CB2受体外，这一发现还促成了两种与大麻素生理学相关蛋白质的鉴定。这些蛋白质是花生四烯酸乙醇胺水解酶（AAH），一种负责花生四烯酸乙醇胺水解分解的酶，以及花生四烯酸乙醇胺转运体（ANT），一种参与花生四烯酸乙醇胺跨细胞膜转运的载体蛋白。目前获得的证据表明，这两种蛋白质共同作用导致花生四烯酸乙醇胺生物活性的终止。此外，花生四烯酸乙醇胺的发现揭示了一类新型的、具有比大麻素稍有不同药理特性的更具选择性的药物。现已报道了许多此类类似物，其中许多与母体配体相比，具有明显提高的大麻素受体亲和力和代谢稳定性。一般来说，花生四烯酸乙醇胺和所有已知类似物对CB1受体具有高亲和力且表现出显著选择性，对CB2受体的亲和力则为中等至非常低。在相对较短的时间内，药理学和生化研究证实了最初的推测，即花生四烯酸乙醇胺要么是一种神经调节剂，要么是一种神经递质，并且极大地推进了我们对大麻素生物化学的理解。本综述旨在界定内源性大麻素的药理学，并聚焦于花生四烯酸乙醇胺对CB1大麻素受体的构效关系（SAR）。
