Waelbroeck M, Hou X, Wehrle J, Mutschler E, Van Tilburg E, Menge W, Timmerman H, Lambrecht G
Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles, Belgium.
Eur J Pharmacol. 1996 May 15;303(3):221-6. doi: 10.1016/0014-2999(96)00038-6.
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 M4 receptors. The three uncharged compounds were muscarinic receptor antagonists, with pA2 or pKi values between 7.9 and 5.6. The achiral ester BS-6181 displayed highest affinity for M1, M3 (Hm3) and M4 receptors (pA2 or pKi = 7.2-7.6) and lower affinity for M2 receptors (pA2 or 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 M4 selective (pKi/M4 = 6.9; pA2 or pKi/M1-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.
我们研究了3,3-二甲基丁-1-醇（胆碱的碳类似物）与二苯乙醇酸、(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]形成的酯在毒蕈碱M1、M2、M3（Hm3）和M4受体上的结合及药理学特性。这三种不带电荷的化合物均为毒蕈碱受体拮抗剂，其pA2或pKi值在7.9至5.6之间。非手性酯BS-6181对M1、M3（Hm3）和M4受体表现出最高亲和力（pA2或pKi = 7.2 - 7.6），对M2受体的亲和力较低（pA2或pKi = 6.7和6.8）。四种毒蕈碱受体亚型能够区分BS-6181的环己基衍生物的两种对映体[(R)-和(S)-BS-7826]，更倾向于(R)-异构体（高达79倍）。有趣的是，作为非优势异构体的BS-7826的(S)-对映体被发现具有M4选择性（pKi/M4 = 6.9；pA2或pKi/M1 - M3（Hm3）= 5.6 - 6.2）。这些结果表明，不带电荷的化合物可能通过疏水相互作用（立体）选择性地结合到毒蕈碱受体上。因此，毒蕈碱配体与受体阴离子位点之间的离子键对于毒蕈碱受体的识别并非绝对必要。
