Stereoselective interaction of uncharged esters at four muscarinic receptor subtypes.
Stereoselective interaction of uncharged esters at four muscarinic receptor subtypes.
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DOI：
10.1016/0014-2999(96)00038-6
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发表时间：
1996-05
影响因子：
5
通讯作者：
M. Waelbroeck;X. Hou;J. Wehrle;E. Mutschler;E. V. van Tilburg;W. Menge;H. Timmerman;G. Lambrecht
中科院分区：
文献类型：
--
作者：
M. Waelbroeck;X. Hou;J. Wehrle;E. Mutschler;E. V. van Tilburg;W. Menge;H. Timmerman;G. Lambrecht
我们研究了 3,3-二甲基丁-1-醇（胆碱的碳类似物）与二苯基乙醇酸、(R)-苯基环己基乙醇酸或 (S)-苯基环己基乙醇酸 [分别为 BS-6181、(R)-BS-7826 和 (S)-BS-7826] 在毒蕈碱 M1、M2、 M3(Hm3) 和 M4 受体。三种不带电荷的化合物是毒蕈碱受体拮抗剂，pA2或pKi值在7.9至5.6之间。非手性酯 BS-6181 对 M1、M3(Hm3) 和 M4 受体 (pA2 或 pKi= 7.2−7.6) 显示出最高的亲和力，对 M2 受体 (pA2 或 pKi= 6.7 和 6.8) 的亲和力较低。四种毒蕈碱受体亚型能够区分 BS-6181 环己基衍生物 [(R)- 和 (S)-BS-7826] 的两种对映体，优先选择 (R)- 异构体（高达 79 倍）。有趣的是，BS-7826 的 (S)-对映体（即反异构体）被发现具有 M4 选择性（p KiM4= 6.9 ；pA2 或 p KiM1-M3(Hm3) = 5.6−6.2）。这些结果表明，不带电荷的化合物可以通过疏水相互作用（立体）选择性地与毒蕈碱受体结合。因此，毒蕈碱配体和受体的阴离子位点之间的离子键对于识别毒蕈碱受体并不是绝对必要的。
We investigated the binding and pharmacological properties of the esters of 3,3-dimethylbutan-1-ol (the carbon analogue of choline) with either diphenylglycolic acid, (R)-phenylcyclohexylglycolic acid, or (S)-phenylcyclohexylglycolic acid [BS-6181, (R)-BS-7826 and (S)-BS-7826, respectively] at muscarinic M1, M2, M3(Hm3) and M4receptors. The three uncharged compounds were muscarinic receptor antagonists, with pA2or pKivalues between 7.9 5.6. The achiral ester BS-6181 displayed highest affinity for M1, M3(Hm3) and M4receptors (pA2or pKi= 7.2−7.6) and lower affinity for M2receptors (pA2or pKi= 6.7 and 6.8). The four muscarinic receptor subtypes were able to distinguish between the two enantiomers of the cyclohexyl derivative of BS-6181 [(R)- and (S)-BS-7826], with a preference for the (R)-isomer (up to 79-fold). Interestingly, the (S)-enantiomer of BS-7826, being the distomer, was found to be M4selective (p KiM4= 6.9 ; pA2or p KiM1-M3(Hm3) = 5.6−6.2). These results indicate that uncharged compounds may (stereo)selectively bind to muscarinic receptors via hydrophobic interactions. Thus, an ionic bond between muscarinic ligands and an anionic site of the receptor is not absolutely necessary for recognition of muscarinic receptors.