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THE INTERACTION OF 4-DAMP MUSTARD WITH SUBTYPES OF THE MUSCARINIC RECEPTOR

机译：4-DAMP芥末与肌肉受体亚型的相互作用

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The compound 4-DAMP mustard (N-2-chloroethyl-4-piperidinyl diphenylacetate) is a 2-chloroethylamine derivative of the selective muscarinic antagonist 4-DAMP (N,N-dimethyl-4-piperidinyl diphenylacetate). At neutral pH, 4-DAMP mustard cyclizes spontaneously into an aziridinium ion that binds covalently with muscarinic receptors. Analysis of the kinetics of receptor alkylation showed that the interaction of 4-DAMP mustard with M(2) and M(3) receptors was consistent with a model in which the aziridinium ion rapidly forms a reversible complex with the receptor which converts to a covalent complex at a relatively slower rate. The rate constant (k(2)) for alkylation of M(2) and M(3) receptors was approximately the same (k(2) = 0.1 min(-1)): however, the affinity of the aziridinium ion for the M(3) receptor (K-D = 7.2 nM) was approximately 6.3-fold greater than that for the M(2) receptor (K-D = 43 nM). The results of competitive binding experiments on Chinese hamster ovary cells transfected with the M(1) - M(5) subtypes of the muscarinic receptor showed that the affinity of the aziridinium ion for the M(1), M(3), M(4) and M(5) subtypes was approximately the same and about 11-fold greater than that for the M(2) receptor. 4-DAMP mustard is a useful tool for selectively inactivating all non-M(2) muscarinic receptors, particularly when it is used in the presence of a reversible M(2) selective antagonist to protect the M(1) receptor from alkylation. The results of studies on isolated smooth muscle preparations that have had their M(3) receptors alkylated with 4-DAMP mustard are consistent with the postulate that the M(2) receptor can elicit contraction by inhibiting the relaxant effect of isoproterenol and forskolin on histamine induced contractions. [References: 39]
机译：化合物4-DAMP芥末（N-2-氯乙基-4-哌啶基二苯基乙酸酯）是选择性毒蕈碱拮抗剂4-DAMP（N，N-二甲基-4-哌啶基二苯基乙酸酯）的2-氯乙胺衍生物。在中性pH值下，4-DAMP芥末会自发环化成与毒蕈碱受体共价结合的叠氮鎓离子。受体烷基化动力学的分析表明，4-DAMP芥子气与M（2）和M（3）受体的相互作用与其中叠氮鎓离子与受体快速形成可逆复合物并转化成共价键的模型相一致。复杂，速度相对较慢。 M（2）和M（3）受体烷基化的速率常数（k（2））大致相同（k（2）= 0.1 min（-1））：但是，叠氮鎓离子对M（3）受体（KD = 7.2 nM）大约比M（2）受体（KD = 43 nM）大6.3倍。对经毒蕈碱受体M（1）-M（5）亚型转染的中国仓鼠卵巢细胞进行竞争性结合实验的结果表明，叠氮鎓离子对M（1），M（3），M（ 4）和M（5）亚型大约相同，并且比M（2）受体大11倍。 4-DAMP芥末酱是一种用于选择性灭活所有非M（2）毒蕈碱受体的有用工具，尤其是当它在可逆M（2）选择性拮抗剂存在下使用以保护M（1）受体免受烷基化时，尤其如此。对分离的平滑肌制剂的M（3）受体已被4-DAMP芥菜烷基化的研究结果与以下假设一致：M（2）受体可通过抑制异丙肾上腺素和毛喉素对组胺的松弛作用而引起收缩诱发收缩。 [参考：39]

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