两种新的哌仑西平类似物对豚鼠食管黏膜肌层对乙酰胆碱、氨甲酰甲胆碱、组胺和高钾的收缩反应的影响。

Effects of two new pirenzepine analogs on the contractile response of the guinea-pig oesophageal muscularis mucosae to acetylcholine, bethanechol, histamine and high potassium.

作者信息

Barocelli E, Morini G, Ballabeni V, Lavezzo A, Impicciatore M

机构信息

Institute of Pharmacology and Pharmacognosy, University of Parma, Italy.

出版信息

Eur J Pharmacol. 1990 Apr 10;179(1-2):89-96. doi: 10.1016/0014-2999(90)90405-u.

DOI:10.1016/0014-2999(90)90405-u

PMID:1973103

Abstract

The guinea-pig oesophageal muscularis mucosae was used to determine the affinity for muscarinic receptors of two new tricyclic compounds, DF 545 and DF 594, which are structurally related to pirenzepine. Both acetylcholine and bethanechol induced a concentration-dependent contraction of the muscularis mucosae. This contraction was competitively antagonized by DF 545 and DF 594 over the dose range 10(-7)-10(-5) M, while at higher concentrations both antagonists caused a depression of the maximal response to the cholinomimetics. The potency of DF 545 and DF 594 appeared to be comparable to that of pirenzepine and approximately 50 times lower than that of atropine. By comparing the affinities of DF 545 and DF 594 with those of selective antagonists (methoctramine and 4-DAMP) which discriminate between M2/M3 muscarinic receptor subtypes, it emerged that pirenzepine as well as DF 545 and DF 594 might act on M3 receptors, which seem to be predominant in the guinea-pig oesophageal muscularis mucosae. McN-A-343 exhibited no agonist activity while it acted as a competitive antagonist against acetylcholine and bethanechol. None of the compounds exhibited calcium antagonist properties. DF 545 inhibited the contractile responses to histamine, but DF 594 and pirenzepine did not.

摘要

豚鼠食管黏膜肌层被用于测定两种新的三环化合物DF 545和DF 594对毒蕈碱受体的亲和力，这两种化合物在结构上与哌仑西平相关。乙酰胆碱和氨甲酰甲胆碱均可引起黏膜肌层浓度依赖性收缩。在10⁻⁷ - 10⁻⁵ M剂量范围内，DF 545和DF 594可竞争性拮抗这种收缩，而在较高浓度时，两种拮抗剂均会使对拟胆碱药的最大反应降低。DF 545和DF 594的效力似乎与哌仑西平相当，比阿托品低约50倍。通过比较DF 545和DF 594与区分M2/M3毒蕈碱受体亚型的选择性拮抗剂（甲溴东莨菪碱和4-二甲基氨基吡啶）的亲和力，发现哌仑西平以及DF 545和DF 594可能作用于M3受体，M3受体似乎在豚鼠食管黏膜肌层中占主导地位。McN-A-343无激动剂活性，但其可作为乙酰胆碱和氨甲酰甲胆碱的竞争性拮抗剂。这些化合物均无钙拮抗剂特性。DF 545可抑制对组胺的收缩反应，但DF 594和哌仑西平则不能。