Eltze M, König H, Ullrich B, Grebe T
Department of Pharmacology, Byk Gulden, Konstanz, Germany.
Eur J Pharmacol. 1997 Jul 30;332(1):77-87. doi: 10.1016/s0014-2999(97)01059-5.
The muscarinic receptor mediating contraction of the guinea-pig isolated gallbladder, currently being disputed to belong either to the M3 or M4 subtype, was characterized by subtype-preferring agonists and discriminating antagonists. Highly significant correlations of agonist potencies to contract the gallbladder, e.g., arecaidine propargyl ester, oxotremorine, 5-methylfurtrethonium > arecoline, arecaidine 2-butyne-1,4-diyl bisester > (R)-nipecotic acid ethyl ester > 4-[[N-(4-chlorophenyl)carbamyl]oxy]-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343), (S)-nipecotic acid ethyl ester > 4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyltrimethylammonium chloride (McN-A-343) were found with muscarinic M3 receptors mediating contraction of the guinea-pig ileum and vasodilation in rat perfused kidney. Functional affinities at guinea-pig gallbladder muscarinic receptors of antagonists known to distinguish between native or cloned muscarinic M3/m3 and M4/m4 receptors, e.g., himbacine, methoctramine, mefurtramine, tripitramine, idaverine, zamifenacin and 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyr ido(2,3-b)(1,4)benzodiazepin-6-one (AQ-RA 741), were consistent with those at guinea-pig ileal muscarinic M3 receptors but not with published data at recently defined muscarinic M4 receptors in rabbit anococcygeus muscle or at muscarinic M1 and M2 receptors in rabbit vas deferens. Antagonist affinities at guinea-pig gallbladder correlated also best with published binding data on native or cloned muscarinic M3/m3 receptors but not with those for muscarinic M4/m4 receptors. The agonist potencies and antagonist affinities suggest that smooth muscle contraction elicited by muscarinic stimuli in guinea-pig gallbladder is mediated by functional muscarinic M3 receptors.
介导豚鼠离体胆囊收缩的毒蕈碱受体，目前对于其属于M3还是M4亚型存在争议，通过亚型选择性激动剂和鉴别性拮抗剂对其进行了表征。例如，激动剂收缩胆囊的效力之间存在高度显著的相关性，如槟榔次碱炔丙酯、氧化震颤素、5-甲基呋索氯铵＞槟榔碱、槟榔次碱2-丁炔-1,4-二基双酯＞（R）-哌啶甲酸乙酯＞4-[[N-（4-氯苯基）氨基甲酰基]氧基]-2-丁炔基三甲基碘化铵（4-Cl-McN-A-343）、（S）-哌啶甲酸乙酯＞4-[[N-（3-氯苯基）氨基甲酰基]氧基]-2-丁炔基三甲基氯化铵（McN-A-343），这些相关性与介导豚鼠回肠收缩和大鼠灌注肾血管舒张的毒蕈碱M3受体的相关性一致。已知可区分天然或克隆的毒蕈碱M3/m3和M4/m4受体的拮抗剂对豚鼠胆囊毒蕈碱受体的功能亲和力，例如，辛巴生、甲溴东莨菪碱、呋索胺、曲匹拉明(安胃灵)、艾达维林、扎非那辛和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），与豚鼠回肠毒蕈碱M3受体的亲和力一致，但与兔肛尾肌中最近定义的毒蕈碱Ml4受体或兔输精管中毒蕈碱M1和M2受体的已发表数据不一致。豚鼠胆囊的拮抗剂亲和力与已发表的关于天然或克隆的毒蕈碱M3/m3受体的结合数据也最相关，但与毒蕈碱M4/m4受体的结合数据不相关。激动剂效力和拮抗剂亲和力表明，豚鼠胆囊中由毒蕈碱刺激引起的平滑肌收缩是由功能性毒蕈碱M3受体介导的。
