Moltzen E K, Pedersen H, Bøgesø K P, Meier E, Frederiksen K, Sánchez C, Løve Lembøl H
H. Lundbeck A/S, Copenhagen-Valby, Denmark.
J Med Chem. 1994 Nov 25;37(24):4085-99. doi: 10.1021/jm00050a006.
A series of arecoline bioisosteres, where the ester group is replaced by a 1,2,3-triazole-4-yl or a tetrazole-5-yl group, was synthesized and evaluated in vitro for affinity and efficacy at muscarinic receptors and in vivo for cholinergic side effects. The corresponding piperidine derivatives were also studied. In the 1,2,3,6-tetrahydropyridyl-1,2,3-triazole series, only derivatives with 2-substituents in the 1,2,3-triazole ring exert muscarinic agonist activity. The same trend is seen in the corresponding tetrazole series, where only 2-substituted derivatives display muscarinic agonist activity. The methyl derivatives in both series are full agonists, whereas the derivatives with longer side chains are partial agonists. Introduction of methyl substituents in the 1,2,3,6-tetrahydropyridine ring generally lowers affinity considerably except for the 3-substituted derivatives, where some activity is retained. In both the 1,2,3-triazole and tetrazole series, derivatives without substituents at the basic nitrogen in the 1,2,3,6-tetrahydropyridine ring are unselective full agonists, whereas the methyl-substituted derivatives generally are more M1 selective compared to M2. Larger substituents than methyl abolish activity. The 4-(3-piperidyl)-1,2,3-triazole and 5-(3-piperidyl)-2H-tetrazole derivatives are generally less active than the corresponding 1,2,3,6-tetrahydropyridine derivatives, and only the 2-allyl- and 2-propargyl-1,2,3-triazole derivatives display activities comparable to the most active compounds in the 1,2,3,6-tetrahydropyridine series. The propargyl derivative is an unselective full agonist, and resolution did not reveal any stereoselectivity The allyl derivative is a partial agonist with some selectivity for the M1 receptor, and testing of the enantiomers showed that the (+)-enantiomer is an unselective partial agonist, whereas the (-)-enantiomer is a partial agonist with preference for the M1 receptor. Generally, the structure-activity relationships of the 1,2,3-triazole and tetrazole series are very similar, and two compounds, 2-ethyl-4-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-1,2,3-triazole and 2-ethyl-5-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-2H-tetrazole, are M1 agonists/M2 antagonists. Muscarinic compounds with this profile are of particular interest as drugs for the treatment of Alzheimer's disease.
合成了一系列槟榔碱生物电子等排体，其中酯基被1,2,3 - 三唑 - 4 - 基或四唑 - 5 - 基取代，并在体外评估了其对毒蕈碱受体的亲和力和效力，在体内评估了其胆碱能副作用。还研究了相应的哌啶衍生物。在1,2,3,6 - 四氢吡啶基 - 1,2,3 - 三唑系列中，只有1,2,3 - 三唑环上有2 - 取代基的衍生物具有毒蕈碱激动剂活性。在相应的四唑系列中也观察到相同的趋势，只有2 - 取代衍生物显示出毒蕈碱激动剂活性。两个系列中的甲基衍生物都是完全激动剂，而侧链较长的衍生物是部分激动剂。在1,2,3,6 - 四氢吡啶环中引入甲基取代基通常会显著降低亲和力，但3 - 取代衍生物除外，其仍保留一些活性。在1,2,3 - 三唑和四唑系列中，1,2,3,6 - 四氢吡啶环上碱性氮无取代基的衍生物是无选择性的完全激动剂，而甲基取代衍生物通常比M2对M1更具选择性。比甲基更大的取代基会消除活性。4 - (3 - 哌啶基) - 1,2,3 - 三唑和5 - (3 - 哌啶基) - 2H - 四唑衍生物通常比相应的1,2,3,6 - 四氢吡啶衍生物活性更低，只有2 - 烯丙基 - 和2 - 炔丙基 - 1,2,3 - 三唑衍生物显示出与1,2,3,6 - 四氢吡啶系列中最具活性的化合物相当的活性。炔丙基衍生物是无选择性的完全激动剂，拆分未显示任何立体选择性。烯丙基衍生物是对M1受体有一定选择性的部分激动剂，对映体测试表明( + ) - 对映体是无选择性的部分激动剂，而( - ) - 对映体是对M1受体有偏好的部分激动剂。一般来说，1,2,3 - 三唑和四唑系列的构效关系非常相似，两种化合物，2 - 乙基 - 4 - (1 - 甲基 - 1,2,3,6 - 四氢 - 5 - 吡啶基) - 1,2,3 - 三唑和2 - 乙基 - 5 - (1 - 甲基 - 1,2,3,6 - 四氢 - 5 - 吡啶基) - 2H - 四唑，是M1激动剂/M2拮抗剂。具有这种特征的毒蕈碱化合物作为治疗阿尔茨海默病的药物特别受关注。
