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2-(3-取代-1,2,4-恶二唑-5-基)-8-甲基-8-氮杂双环[3.2.1]辛烷和2α-(3-取代-1,2,4-恶二唑-5-基)-8-甲基-8-氮杂双环[3.2.1]辛-2-烯作为潜在毒蕈碱激动剂的合成

Synthesis of 2-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo [3.2.1]octanes and 2 alpha-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-enes as potential muscarinic agonists.

作者信息

Triggle D J, Kwon Y W, Abraham P, Rahman M A, Carroll F I

机构信息

Department of Biochemical Pharmacology, School of Pharmacy, State University of New York, Buffalo 14260.

出版信息

Pharm Res. 1992 Nov;9(11):1474-9. doi: 10.1023/a:1015871131913.

DOI:10.1023/a:1015871131913
PMID:1475236
Abstract

Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [3H]QNB and [3H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10(-6) and 1.79 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10(-4) M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo- [3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.

摘要

已在大鼠心脏、大鼠脑以及转染了m1或m3的CHO细胞膜制剂中测定了七种具有恶二唑环侧链的毒蕈碱受体配体的放射性配体结合亲和力，以确定其对毒蕈碱受体亚型的选择性。测量脑膜中结合常数的比率，作为针对[3H]QNB和[3H]Oxo-M的潜在激动剂活性指标。这些毒蕈碱配体无法区分毒蕈碱受体的亚型。六种在8-甲基-8-氮杂双环[3.2.1]辛-2-烯或8-甲基-8-氮杂双环[3.2.1]辛烷头部基团上连接有3-氨基-或3-甲基-1,2,4-恶二唑-5-基的毒蕈碱配体，在大鼠心脏、大鼠脑以及转染了m1或m3的CHO细胞膜制剂中的结合常数在2.2×10⁻⁶至1.79×10⁻⁵M之间。1-甲基-2-[3-氨基-1,2,4-恶二唑-5-基]哌啶在大鼠心脏和大鼠脑中显示出约10⁻⁴M的低结合常数。(1R,5S)-2-[3-氨基-1,2,4-恶二唑-5-基]-8-甲基-8-氮杂双环-[3.2.1]辛-2-烯[(1R,5S)-17]是活性最高的化合物。

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