Pertwee R G, Griffin G, Lainton J A, Huffman J W
Department of Biomedical Sciences, Marischal College, University of Aberdeen, Scotland, UK.
Eur J Pharmacol. 1995 Sep 25;284(3):241-7. doi: 10.1016/0014-2999(95)00318-f.
The novel compounds, 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoy)indole, produced a dose-related inhibition of electrically evoked contractions of the mouse vas deferens, with IC50 values of 2.56 nM, 3.38 nM and 639 nM respectively. Kd values of the selective CB1 cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride], determined in the vas deferens from experiments with these compounds are 1.34 nM, 3.86 nM and 8.06 nM respectively, indicating their susceptibility to antagonism by SR141716A is similar to that of their parent compound, the CB1 cannabinoid receptor agonist WIN 55,212-2 ¿(R)-(+)-2,3-dihydro-5-methyl-3-[4-methylino)methyl]pyrrolo-[1,2, 3-de]-1,4-benzoxazin-6-ylmethanone}. SR141716A (100 nM) had no effect on the actions of two non-cannabinoid receptor agonists, morphine and clonidine. These results provide strong support for the hypothesis that 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole are cannabinoid receptor agonists and confirm that the WIN 55,212-2 molecule can be modified considerably without detectable loss of cannabinoid activity.
新型化合物1-戊基-2-甲基-3-(1-萘甲酰基)吲哚、1-戊基-3-(1-萘甲酰基)吡咯和1-庚基-3-(1-萘甲酰基)吲哚对小鼠输精管的电诱发收缩产生剂量相关的抑制作用，IC50值分别为2.56 nM、3.38 nM和639 nM。在输精管实验中，用这些化合物测定的选择性CB1大麻素受体拮抗剂SR141716A [N-(哌啶-1-基)-5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酰胺盐酸盐]的Kd值分别为1.34 nM、3.86 nM和8.06 nM，表明它们对SR141716A拮抗作用的敏感性与其母体化合物CB1大麻素受体激动剂WIN 55,212-2 [R-(+)-2,3-二氢-5-甲基-3-[4-甲基亚氨基)甲基]吡咯并-[1,2,3-de]-1,4-苯并恶嗪-6-基甲酮]相似。SR141716A（100 nM）对两种非大麻素受体激动剂吗啡和可乐定的作用没有影响。这些结果为以下假设提供了有力支持：1-戊基-2-甲基-3-(1-萘甲酰基)吲哚、1-戊基-3-(1-萘甲酰基)吡咯和1-庚基-3-(1-萘甲酰基)吲哚是大麻素受体激动剂，并证实WIN 55,212-2分子可以在不显著丧失大麻素活性的情况下进行相当大程度的修饰。
