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首页> 外文期刊>Life sciences >THE DESIGN AND PHARMACOLOGY OF NOVEL SELECTIVE MUSCARINIC AGONISTS AND ANTAGONISTS
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THE DESIGN AND PHARMACOLOGY OF NOVEL SELECTIVE MUSCARINIC AGONISTS AND ANTAGONISTS

机译：新型选择性肌肉药物和拮抗剂的设计与药理作用

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The muscarinic pharmacology of Cl-methyl-substituted chiral compounds related to McN-A-343 and of(R)- and (S)-dimethindene has been studied. Among the McN-A-343 analogues, the (S)-enantiomers were more potent and had higher affinity than the (R)-isomers. The quaternary compound (S)-BN 228 was found to be the most potent M(1)-selective agonist known today (pEC(50): M(I)/rabbit vas deferens = 7.83; M(2)/guinea-pig atria = 6.35; M(3)/guinea-pig ileum = 6.29). In both the atria and ileum the tertiary carbamate, (S)-4-F-MePyMcN, was a competitive antagonist (pA(2) value = 7.39 and 6.82, respectively). In contrast, in rabbit vas deferens (S)-4-F-MePyMcN was a potent partial agonist (pEC(50) = 7.22; apparent efficacy = 0.83). These results indicate that (S)-4-F-MePyMcN might be a useful tool to study M(1) receptor-mediated effects involved in central cholinergic function. (S)-Dimethindene was a potent M(2)-selective antagonist (pA(2) = 7.86/atria; pK(i) = 7.8/rat heart) with lower affinities for the M(1) (pA(2) = 6.36/rat duodenum; pK(i) = 7.1/NB-OK 1 cells), M(3) (pA(2) = 6.92/guinea-pig ileum; pK(i) = 6.7/rat pancreas) and Mg receptors (pK(i) = 7.0/rat striatum). It was more potent (up to 41-fold) than the (R)-isomer. In contrast, the stereoselectivity was inverse at ileal H-1 receptors (pA(2): (R)-isomer = 9.42; (S)-isomer = 7.48). Thus, (S)-dimethindene could be a valuable agent to test the hypothesis that M(2) antagonists show beneficial effects in the treatment of cognitive disorders. It might also become the starting point for the development of diagnostic tools for quantifying M(2) receptors in the CNS with PET imaging. [References: 22]
机译：已经研究了与McN-A-343和（R）-和（S）-二甲茚有关的Cl-甲基取代的手性化合物的毒蕈碱药理学。在McN-A-343类似物中，（S）-对映异构体比（R）-异构体更有效且亲和力更高。季化合物（S）-BN 228被发现是当今已知最有效的M（1）选择性激动剂（pEC（50）：M（I）/兔输精管= 7.83; M（2）/豚鼠心房= 6.35; M（3）/豚鼠回肠= 6.29）。在心房和回肠中，叔氨基甲酸酯（S）-4-F-MePyMcN是竞争性拮抗剂（pA（2）值分别为7.39和6.82）。相反，在兔输精管（S）-4-F-MePyMcN是一种有效的部分激动剂（pEC（50）= 7.22;表观功效= 0.83）。这些结果表明，（S）-4-F-MePyMcN可能是研究中枢胆碱能功能涉及的M（1）受体介导作用的有用工具。 （S）-二甲茚是一种有效的M（2）-选择性拮抗剂（pA（2）= 7.86 / atria; pK（i）= 7.8 /大鼠心脏），对M（1）的亲和力较低（pA（2）= 6.36 /大鼠十二指肠; pK（i）= 7.1 / NB-OK 1细胞），M（3）（pA（2）= 6.92 /豚鼠回肠; pK（i）= 6.7 /大鼠胰腺））和Mg受体（ pK（i）= 7.0 /大鼠纹状体）。它比（R）异构体更有效（最多41倍）。相反，在回肠H-1受体上立体选择性相反（pA（2）：（R）-异构体= 9.42;（S）-异构体= 7.48）。因此，（S）-二甲双烯可能是一种有价值的试剂，以检验以下假设：M（2）拮抗剂在认知障碍的治疗中显示出有益的作用。它也可能成为开发诊断工具以定量PET成像中枢神经系统中M（2）受体的起点。 [参考：22]

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