Comparative pharmacology of recombinant human M3 and M5 muscarinic receptors expressed in CHO‐K1 cells
Comparative pharmacology of recombinant human M3 and M5 muscarinic receptors expressed in CHO‐K1 cells
复制标题
CHO-K1 细胞中表达的重组人 M3 和 M5 毒蕈碱受体的药理学比较
DOI：
10.1038/sj.bjp.0702551
复制
发表时间：
1999
影响因子：
7.3
通讯作者：
S. Hegde
中科院分区：
文献类型：
--
作者：
N. Watson;D. V. Daniels;A. Ford;R. Eglen;S. Hegde
获得了几种毒蕈碱拮抗剂对稳定表达人毒蕈碱M3或M5受体亚型的中国仓鼠卵巢（CHO-K1）细胞中卡巴胆碱刺激的[3 H]-肌醇磷酸蓄积的亲和力估计值。这些研究的基本原理是生成M5受体亚型的功能性拮抗剂亲和力谱，并将其与M3受体的亲和力谱进行比较，以鉴定区分这两种亚型的化合物。毒蕈碱M5受体的拮抗剂表观亲和力（pKB）的等级顺序为阿托品（8.7）托特罗定（8.6）=4-二苯基乙酰氧基-N-甲基哌啶（4-DAMP，8.6）>达非那新（7.7）扎米那新（7.6）>奥昔布宁（6.6）=帕拉氟六氢硅地芬尼多（p-F-HSiD，6.6）>哌仑西平（6.4）甲氧曲明（6.3）=辛巴辛（6.3）> AQ-RA 741（6.1）。 拮抗剂对两种受体亚型的表观亲和力与已发表的结合亲和力估计值相当。没有拮抗剂对毒蕈碱M5亚型显示出比M3亚型更高的选择性，但喜巴辛、AQ-RA 741、p-F-HHSiD、达非那新和奥昔布宁对毒蕈碱M3亚型显示出比M5亚型高9 - 60倍的选择性。 这项研究突出了M3和M5受体亚型的药理学特征的相似性，并确定了五种拮抗剂，这些拮抗剂可能代表区分这两种亚型的有用工具。总的来说，这些数据表明，在不存在高亲和力M5选择性拮抗剂的情况下，大范围拮抗剂的亲和力数据对于可操作地定义M5受体亚型是至关重要的。
Affinity estimates were obtained for several muscarinic antagonists against carbachol‐stimulated [3H]‐inositol phosphates accumulation in Chinese hamster ovary (CHO‐K1) cells stably expressing either human muscarinic M3 or M5 receptor subtypes. The rationale for these studies was to generate a functional antagonist affinity profile for the M5 receptor subtype and compare this with that of the M3 receptor, in order to identify compounds which discriminate between these two subtypes. The rank order of antagonist apparent affinities (pKB) at the muscarinic M5 receptor was atropine (8.7)tolterodine (8.6)=4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP, 8.6)>darifenacin (7.7)zamifenacin (7.6)>oxybutynin (6.6)=para‐fluorohexahydrosiladifenidol (p‐F‐HHSiD, 6.6)>pirenzepine (6.4)methoctramine (6.3)=himbacine (6.3)>AQ‐RA 741 (6.1). Antagonist apparent affinities for both receptor subtypes compare well with published binding affinity estimates. No antagonist displayed greater selectivity for the muscarinic M5 subtype over the M3 subtype, but himbacine, AQ‐RA 741, p‐F‐HHSiD, darifenacin and oxybutynin displayed between 9‐ and 60 fold greater selectivity for the muscarinic M3 over the M5 subtype. This study highlights the similarity in pharmacological profiles of M3 and M5 receptor subtypes and identifies five antagonists that may represent useful tools for discriminating between these two subtypes. Collectively, these data show that in the absence of a high affinity M5 selective antagonist, affinity data for a large range of antagonists is critical to define operationally the M5 receptor subtype.
DOI：
--
发表时间：
1992-02
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
C. Bolden;B. Cusack;Elliott Richelson
通讯作者：
C. Bolden;B. Cusack;Elliott Richelson