Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder
Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder
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DOI：
10.1016/s0022-5347(05)00017-0
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发表时间：
2006-01-01
影响因子：
6.6
通讯作者：
Yamada, S
中科院分区：
文献类型：
--
作者：
Maruyama, S;Oki, T;Yamada, S
目的：我们表征了几种抗毒蕈碱剂在人毒蕈碱受体上的结合亲和力。材料和方法：抗毒蕈碱剂对特异性NMS [H-3]的竞争性抑制作用（PerkinElmer Life Sciences，Boston，马萨诸塞州）结合。奥昔布宁、丙哌维林、托特罗定、各自的代谢物DEOB、DPr-P-4（N -> O）和5-HM，和达非那新以浓度依赖性方式抑制人膀胱和腮腺匀浆以及CHO细胞膜中的特异性[H-3]NMS结合。表达人毒蕈碱M1至M1受体亚型的K1细胞系。基于抑制常数值，托特罗定、5-HM和DPr-P-4（N -> O）的抑制作用在膀胱中比在腮腺中大1.4至1.7倍，而奥昔布宁、DEOB、丙哌维林和达非那新的抑制作用在腮腺中大2至10倍。因此，与奥昔布宁、DEOB、丙哌维林和达非那新相比，托特罗定、5-HM和DPr-P-4（N -> O）在人膀胱中显示出比在腮腺中高3至4倍的对毒蕈碱受体的亲和力。托特罗定和5-HM在抑制表达M1亚型的细胞膜上特异性[H-3]NMS结合方面的效力是M1亚型的2倍。相反，奥昔布宁，DEOB，丙哌维林，DPr-P-4（N -> O）和达非那新表现出2至22倍高亲和力的M，比M-2 subtype.Conclusions：与奥昔布宁相比，托特罗定，5-HM和DPr-P-4（N -> O）可能更有选择性地结合到人膀胱中的毒蕈碱受体比在腮腺中。
Purpose: We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors.Materials and Methods: Competitive inhibitory effects of antimuscarinic agents on specific NMS [H-3] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes.Results: Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N -> O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [H-3]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M, to M, receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N -> O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N -> O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [H-3]NMS binding at cell membranes expressing the M, vs the M, subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N -> O) and darifenacin showed 2 to 22 times higher affinity to the M, than to the M-2 subtype.Conclusions: Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N -> O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland.