Sauerberg P, Falch E, Meier E, Lembøl H L, Krogsgaard-Larsen P
Department of Chemistry BC, Royal Danish School of Pharmacy, Copenhagen.
J Med Chem. 1988 Jul;31(7):1312-6. doi: 10.1021/jm00402a010.
A number of S-methylsulfonium analogues of the conformationally restricted muscarinic agonists of the 3-alk-oxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine (O-alkyl-THPO) type have been synthesized. The effects on muscarinic receptors of these 3-alkoxy-5-methyl-6,7-dihydro-4H-thiopyrano[3,4-d]isoxazol-5 -ium (O-alkyl-S-methyl-DHTO) analogues (7a-d) were assessed in receptor-binding experiments with tritiated oxotremorine M, pirenzepine, and quinuclidinyl benzilate as ligands and were supported by studies on the isolated guinea pig ileum. The degree of muscarinic agonist activity of the compounds (M-agonist index) and their selectivity for M-1 or M-2 muscarinic receptor subtypes (M-2/M-1 index) were estimated on the basis of receptor-binding studies. The in vitro pharmacological profiles of the compounds were compared with those of arecoline and its sulfonium and 3-methoxyisoxazole isosteres, sulfoarecoline and O,5-dimethyl-THPO, respectively. While O-methyl-DHTO (5a) and N-methyl-DHTO (6a) were inactive, all of the sulfonium analogues 7a-d were muscarinic agonists with the exception of O-ethyl-S-methyl-DHTO (7b), which showed a muscarinic antagonist profile.
已合成了多种3-烷氧基-4,5,6,7-四氢异恶唑并[4,5-c]吡啶（O-烷基-THPO）型构象受限的毒蕈碱激动剂的S-甲基锍类似物。在以氚标记的氧震颤素M、哌仑西平及樟柳碱为配体的受体结合实验中评估了这些3-烷氧基-5-甲基-6,7-二氢-4H-硫代吡喃并[3,4-d]异恶唑-5-鎓（O-烷基-S-甲基-DHTO）类似物（7a-d）对毒蕈碱受体的作用，并得到了对豚鼠离体回肠研究的支持。基于受体结合研究估算了化合物的毒蕈碱激动剂活性程度（M-激动剂指数）及其对M-1或M-2毒蕈碱受体亚型的选择性（M-2/M-1指数）。将这些化合物的体外药理学特征分别与槟榔碱及其锍类似物以及3-甲氧基异恶唑电子等排体、磺基槟榔碱和O,5-二甲基-THPO的药理学特征进行了比较。虽然O-甲基-DHTO（5a）和N-甲基-DHTO（6a）无活性，但除显示出毒蕈碱拮抗剂特征的O-乙基-S-甲基-DHTO（7b）外，所有锍类似物7a-d均为毒蕈碱激动剂。
