Felder C C, Joyce K E, Briley E M, Glass M, Mackie K P, Fahey K J, Cullinan G J, Hunden D C, Johnson D W, Chaney M O, Koppel G A, Brownstein M
Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland, USA.
J Pharmacol Exp Ther. 1998 Jan;284(1):291-7.
LY320135 is a selective antagonist for the brain CB1 receptor, having greater than 70-fold higher affinity for the CB1 than the peripheral CB2 receptor. The Ki values for LY320135 at the CB1 and CB2 receptors, transfected and stably expressed in cell lines, were 224 nM and > 10 microM, respectively. Similar Ki values were measured in binding studies performed on cerebellum and spleen membrane preparations endogenously expressing the CB1 (203 nM) and CB2 (> 10 microM) receptors, respectively. LY320135 functionally reversed anandamide-mediated adenylate cyclase inhibition in Chinese hamster ovary (CHO) cells stably expressing the CB1 receptor. Pertussis toxin treatment of CHO cells expressing the CB1 receptor attenuated the anandamide-mediated inhibition of adenylate cyclase and unmasked a stimulatory effect of anandamide on adenylate cyclase. The stimulatory component was blocked with LY320135. This compound also blocked WIN 55212-2-mediated inhibition of N-type calcium channels and activation of inwardly rectifying potassium channels in N18 and AtT-20-CB2 cells, respectively. LY320135 is a promising lead compound for the further development of novel, potent and selective cannabinoid antagonists of novel structure.
LY320135是一种脑CB1受体的选择性拮抗剂，对CB1受体的亲和力比对外周CB2受体高70多倍。在细胞系中稳定表达的CB1和CB2受体上，LY320135的Ki值分别为224 nM和>10 μM。在内源性表达CB1（203 nM）和CB2（>10 μM）受体的小脑和脾脏膜制剂上进行的结合研究中，测得的Ki值相似。LY320135在功能上逆转了稳定表达CB1受体的中国仓鼠卵巢（CHO）细胞中花生四烯酸乙醇胺介导的腺苷酸环化酶抑制作用。用百日咳毒素处理表达CB1受体的CHO细胞可减弱花生四烯酸乙醇胺介导的腺苷酸环化酶抑制作用，并揭示花生四烯酸乙醇胺对腺苷酸环化酶的刺激作用。刺激成分被LY320135阻断。该化合物还分别阻断了WIN 55212-2介导的N18细胞中N型钙通道的抑制作用和AtT-20-CB2细胞中内向整流钾通道的激活作用。LY320135是一种有前景的先导化合物，可用于进一步开发新型、强效和选择性的新型结构大麻素拮抗剂。
