N(G)-NITRO L-ARGININE METHYL-ESTER AND OTHER ALKYL ESTERS OF ARGININE ARE MUSCARINIC RECEPTOR ANTAGONISTS
N(G)-NITRO L-ARGININE METHYL-ESTER AND OTHER ALKYL ESTERS OF ARGININE ARE MUSCARINIC RECEPTOR ANTAGONISTS
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DOI：
10.1161/01.res.72.2.387
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发表时间：
1993-02-01
影响因子：
20.1
通讯作者：
KEEF, KD
中科院分区：
文献类型：
--
作者：
BUXTON, ILO;CHEEK, DJ;KEEF, KD
在分子的末端胍基氮和/或羧基末端具有修饰的L-精氨酸类似物由于其抑制一氧化氮产生的能力而被广泛使用，并且被认为是一氧化氮合酶的竞争性拮抗剂。本研究旨在测试这些药物也是毒蕈碱受体拮抗剂的可能性。乙酰胆碱使去内皮兔冠状动脉和离体犬结肠平滑肌条产生浓度依赖性收缩。精氨酸类似物N（G）-硝基L-精氨酸甲酯（L-NAME，100 μ M）而不是N（G）-单甲基L-精氨酸（L-NMMA，100 μ M）使这些收缩关系显著向右移动，这种作用不能被加入1 mM L-精氨酸逆转。在使用毒蕈碱放射性配体[H-3]奎宁环基二苯乙酸酯和已知含有M1、M2和M3毒蕈碱受体的不同贡献的组织的放射性配体结合研究中，增加浓度的L-NAME导致结合的双相竞争，亲和力（K（i））范围从内皮中的68 μ M到整个主动脉中的317 μ M。加入抗水解的鸟苷5 '-三磷酸类似物GTP γ S（100 μ M）对[H-3]奎宁环基二苯甲酸酯结合的L-NAME竞争没有影响。在使用激动剂卡巴胆碱的放射性配体结合竞争研究中添加L-NAME并未导致受体对激动剂的亲和力改变，证实了L-NAME与毒蕈碱受体相互作用的竞争性质。在放射性配体结合实验中，评价了在分子羧基末端具有烷基酯修饰的几种L-精氨酸类似物以及没有这种修饰的L-精氨酸类似物作为毒蕈碱拮抗剂。只有那些精氨酸化合物与修饰的羧基能够竞争放射性配体结合的毒蕈碱受体。我们的研究结果表明，L-精氨酸的烷基酯是毒蕈碱拮抗剂，并表明这些化合物是不良的选择，作为一氧化氮合酶抑制剂的研究中，毒蕈碱受体不被阻断。
Analogues Of L-arginine with modifications at the terminal guanidino nitrogen and/or the carboxyl terminus of the molecule have been widely used for their ability to inhibit the production of nitric oxide and are thought to be competitive antagonists of nitric oxide synthase. The present studies were designed to test the possibility that these agents are also muscarinic receptor antagonists. Acetylcholine produced concentration-dependent contraction of endothelium-denuded rabbit coronary artery as well as isolated strips of canine colonic smooth muscle. The arginine analogue N(G)-nitro L-arginine methyl ester (L-NAME, 100 muM) but not N(G)-monomethyl L-arginine (L-NMMA, 100 muM) significantly shifted these contractile relations to the right, an effect that was not reversed by addition of 1 mM L-arginine. In radioligand binding studies using the muscarinic radioligand [H-3]quinuclidinyl benzilate and tissues known to contain differing contributions of M1, M2, and M3 muscarinic receptors, addition of increasing concentrations of L-NAME resulted in a monophasic competition of binding with affinities (K(i)) ranging from 68 muM in endothelium to 317 muM in whole aorta. Addition of the hydrolysis-resistant guanosine 5'-triphosphate analogue GTPgammaS (100 muM) had no effect on L-NAME competition of [H-3]quinuclidinyl benzilate binding. Addition of L-NAME in radioligand binding competition studies using the agonist carbachol did not result in an alteration of the receptor's affinity for agonist, confirming the competitive nature of the interaction of L-NAME with the muscarinic receptor. Several L-arginine analogues with alkyl ester modifications at the carboxyl end of the molecule as well as those without this modification were evaluated as muscarinic antagonists in radioligand binding experiments. Only those arginine compounds with a modified carboxyl group were able to compete for radioligand binding to the muscarinic receptor. Our results indicate that alkyl esters Of L-arginine are muscarinic antagonists and suggest that these compounds are poor choices as nitric oxide synthase inhibitors in studies in which muscarinic receptors are not blocked.