Woodward D F, Carling R W C, Cornell C L, Fliri H G, Martos J L, Pettit S N, Liang Y, Wang J W
Allergan Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
Pharmacol Ther. 2008 Oct;120(1):71-80. doi: 10.1016/j.pharmthera.2008.08.001. Epub 2008 Aug 6.
The discovery of anandamide and 2-arachidonyl glycerol (2-AG) as naturally occurring mammalian endocannabinoids has had important and wide-reaching therapeutic implications. This, to a large extent, ensues from the complexity of endocannabinoid biology. One facet of endocannabinoid biology now receiving increased attention is the cyclo-oxygenase-2 (COX-2) derived oxidation products. Anandamide and 2-AG are oxidized to a range of PG-ethanolamides and PG-glyceryl esters that closely approaches that of the prostaglandins (PGs) formed from arachidonic acid. The pharmacology of these electrochemically neutral PG-ethanolamides (prostamides) and PG-glyceryl esters appears to be unique. No meaningful interaction with natural or recombinant prostanoid receptors is apparent. Nevertheless, in certain cells and tissues, prostamides and PG-glyceryl esters exert potent effects. The recent discovery of selective antagonists for the putative prostamide receptor has been a major advance in further establishing prostamide pharmacology as an entity distinct from prostanoid receptors. Since discovery of the prototype prostamide antagonist (AGN 204396), rapid progress has been made. The latest prostamide antagonists (AGN 211334-6) are 100 times more potent than the prototype and are, therefore, sufficiently active to be used in living animal studies. These compounds will allow a full evaluation of the role of prostamides in health and disease. To date, the only therapeutic application for prostamides is in glaucoma. The prostamide analog, bimatoprost, being the most effective ocular hypotensive drug currently available. Interestingly, PGE(2)-glyceryl ester and its chemically stable analog PGE(2)-serinolamide also lower intraocular pressure in dogs. Nevertheless, the therapeutic future of PGE(2)-glyceryl ester is more likely to reside in inflammation.
花生四烯乙醇胺和2-花生四烯酸甘油酯（2-AG）作为天然存在的哺乳动物内源性大麻素的发现，具有重要且影响深远的治疗意义。这在很大程度上源于内源性大麻素生物学的复杂性。内源性大麻素生物学中一个目前受到越来越多关注的方面是环氧化酶-2（COX-2）衍生的氧化产物。花生四烯乙醇胺和2-AG被氧化为一系列PG-乙醇酰胺和PG-甘油酯，其种类与由花生四烯酸形成的前列腺素（PGs）非常接近。这些电化学中性的PG-乙醇酰胺（前列腺酰胺）和PG-甘油酯的药理学似乎是独特的。与天然或重组前列腺素受体没有明显的有意义的相互作用。然而，在某些细胞和组织中，前列腺酰胺和PG-甘油酯发挥着强大的作用。最近发现了假定的前列腺酰胺受体的选择性拮抗剂，这是在进一步确立前列腺酰胺药理学作为一个与前列腺素受体不同的实体方面的一项重大进展。自从发现原型前列腺酰胺拮抗剂（AGN 204396）以来，已经取得了迅速的进展。最新的前列腺酰胺拮抗剂（AGN 211334 - 6）的效力比原型强100倍，因此具有足够的活性可用于活体动物研究。这些化合物将使人们能够全面评估前列腺酰胺在健康和疾病中的作用。迄今为止，前列腺酰胺唯一的治疗应用是在青光眼方面。前列腺酰胺类似物比马前列素是目前可用的最有效的降眼压药物。有趣的是，PGE(2)-甘油酯及其化学稳定的类似物PGE(2)-丝氨醇酰胺在狗身上也能降低眼压。然而，PGE(2)-甘油酯的治疗前景更可能在于炎症方面。
