Weiser M, Mutschler E, Lambrecht G
Pharmakologisches Institut für Naturwissenschaftler, Biozentrum Niederursel, Universität Frankfurt, M., Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Nov;356(5):671-7. doi: 10.1007/pl00005104.
The present study was designed to characterize the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle by means of a series of muscarinic agonists and subtype-preferring key muscarinic antagonists. Cumulative addition of muscarinic agonists elicited concentration-dependent contractions with the following rank order of potency (pD2 values): (+)-muscarine (6.36) > or = oxotremorine M (6.21) > or = arecaidine propargyl ester (APE) (6.18) > carbachol (5.68) = (+/-)-methacholine (5.65) > 4-(4-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride (4-Cl-McN-A-343) (4.28) > 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) (3.89). (+)-Muscarine, oxotremorine M, carbachol and (+/-)-methacholine behaved as full agonists, whereas APE, 4-Cl-McN-A-343 and McN-A-343 displayed partial agonism. The contractile responses of the rat anococcygeus muscle to (+/-)-methacholine were competitively antagonized by pirenzepine (pA2 = 6.92), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl] 5,11-dihydro-6H-pyrido(2,3-b) (1,4)-benzodiazepine-6-one (AQ-RA 741; pA2 = 6.75), himbacine (pA2 = 7.11), (+/-)-p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD; pA2 = 7.68) and the (R)- and (S)-enantiomers of hexahydro-difenidol [(R)-HHD: pA2 = 8.52; (S)-HHD: pA2 = 6.06]. A comparison of the pA2 values derived from studies of contraction in rat anococcygeus muscle with literature binding (pKi values) and functional affinities (pA2 values) obtained at native M1-M4 receptors strongly suggests that the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle are of the M3 subtype.
本研究旨在通过一系列毒蕈碱激动剂和亚型选择性关键毒蕈碱拮抗剂来表征介导大鼠肛门尾骨肌收缩的节后毒蕈碱受体。累积添加毒蕈碱激动剂可引发浓度依赖性收缩，其效价顺序如下（pD2值）：（+）-毒蕈碱（6.36）≥氧化震颤素M（6.21）≥槟榔碱炔丙基酯（APE）（6.18）＞卡巴胆碱（5.68）=（±）-醋甲胆碱（5.65）＞4-（4-氯苯基-氨甲酰氧基）-2-丁炔基三甲基氯化铵（4-Cl-McN-A-343）（4.28）＞4-（3-氯苯基氨甲酰氧基）-2-丁炔基三甲基氯化铵（McN-A-343）（3.89）。（+）-毒蕈碱、氧化震颤素M、卡巴胆碱和（±）-醋甲胆碱表现为完全激动剂，而APE、4-Cl-McN-A-343和McN-A-343表现为部分激动作用。大鼠肛门尾骨肌对（±）-醋甲胆碱的收缩反应被哌仑西平（pA2 = 6.92）、11-[[4-[4-（二乙氨基）丁基]-1-哌啶基]乙酰基]5,11-二氢-6H-吡啶并（2,3-b）（1,4）-苯并二氮杂卓-6-酮（AQ-RA 741；pA2 = 6.75）、辛可卡因（pA2 = 7.11）、（±）-对氟-六氢硅二苯二醇（p-F-HHSiD；pA2 = 7.68）以及六氢二苯二醇的（R）-和（S）-对映体[（R）-HHD：pA2 = 8.52；（S）-HHD：pA2 = 6.06]竞争性拮抗。将大鼠肛门尾骨肌收缩研究得出的pA2值与在天然M1-M4受体处获得的文献结合（pKi值）和功能亲和力（pA2值）进行比较，强烈表明介导大鼠肛门尾骨肌收缩的节后毒蕈碱受体为M3亚型。
