Synthesis of Conformationally Constrained Analogues of Epibatidine and Development of Non-opioidal Analgesics

依巴替丁构象受限类似物的合成及非阿片类镇痛药的开发

• 批准号: 12557203
• 负责人: KIBAYASHI Chihiko
• 金额: $ 4.22万
• 依托单位: Tokyo University of Pharmacy and Life Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557203/
• 关键词: Dendrobatid alkaloid; epibatidine; non-opioidal analgesic agent; oxaspirocyclic analogues; internitrogen distance; nicotinic acetylcholine receptor; binding affinity; 配座固定アナログ; 非麻薬性鎮痛薬; スピロ化合物; 不斉合成; ヘテロディールス-アルダー反応

We have developed a synthetic method to prepare the conformationally constrained spirodihydrofuropyridines as syn-N-N and anti-N-N analogues of epibatidine, in which the 7-azabicyclo[2.2.1] heptane system and the 2-choropyridine ring are held rigidly with the shorter and longer N-N distances, respectively. The synthesis of the syn-N-N analogue was achieved via the reaction of N-Boc-7-azabicyclo[2.2.1]heptan-2-one with 2-chloro-5-lithio-4-methylpyridine to give the endo-alcohol as a single isomer, which underwent bromination with NBS, basic treatment to form the oxaspirocyclic compound, and deportection of the N-Boc group. The anti-N-N analogue was obtained in a similar way by using 6-chloro-3-lithio-2-methylpyridine.Binding assays conducted in brain membranes of male Wister rats by measuring the displacement of [3H]cytisine showed that the syn-N-N spiro analogue with the shorter N-N distance has at least two-fold stronger binding affinity (IC_<50> = 409 nM, Ki = 136 nM) for nAChRs than the anti-N-Nanalogue (IC_50 = >1000 nM) containing the longer internitrogen distance. The binding studies of these analogues imply that the epibatidine conformer with the shorter N-N distance is favored for high affinity for the central nicotinic acetylcholine binding sites, which would provide some insight into the development of a rational approach for the design and preparation of new ligands selective for the central nAChRs.

我们发展了一种合成方法来制备具有构象约束的螺二氢呋喃并吡啶类化合物作为地棘蛙素的顺式-N-N和反式-N-N类似物，其中7-氮杂双环[2.2.1]庚烷体系和2-氯吡啶环分别以较短和较长的N-N距离刚性保持。顺式-N-N类似物的合成是通过N-Boc-7-氮杂双环[2.2.1]庚-2-酮与2-氯-5-锂-4-甲基吡啶反应得到单一异构体的内醇，其经NBS溴化，碱处理形成氧杂螺环化合物，并脱除N-Boc基团来实现的。通过测定[~ 3 H]金雀花碱的位移在雄性Wister大鼠的脑细胞膜中进行的结合试验表明，具有较短N-N距离的顺式-N-N螺类似物对nAChRs的结合亲和力（IC_（50<50>）= 409 nM，Ki = 136 nM）比具有较长氮间距离的抗-N-Nanostrant（IC_（50）= &gt;1000 nM）强至少两倍。这些类似物的结合研究表明，具有较短的N-N距离的epibatidine构象有利于中央烟碱乙酰胆碱结合位点的高亲和力，这将提供一些洞察到一个合理的方法的发展设计和制备新的配体选择性的中央nAChRs。

项目成果

Hideki Abe, Yumiko Arai, Sakae Aoyagi, and Chihiro Kibayashi,: "Synthesis of Conformationally Constrained Spirodihydrofuropyridine Analogues of Epibatidine"Tetrahedron Letter.. 44(14). 2971-2973 (2003)

Hideki Abe、Yumiko Arai、Sakae Aoyagi 和 Chihiro Kibayashi，“Epibatidine 的构象约束螺二氢呋喃吡啶类似物的合成”四面体信件.. 44(14)。

Hideki Abe, Yumiko Arai, Sakae Aoyagi, Chihiro Kibayashi: "Synthesis of Conformationally Constrained Spirodihydrofuropyridine Analogues of Epibatidine"Tetrahedron Letter. 44(14). 2971-2973 (2003)

Hideki Abe、Yumiko Arai、Sakae Aoyagi、Chihiro Kibayashi：“Epibatidine 的构象约束螺二氢呋喃吡啶类似物的合成”四面体字母。