Synthesis of Conformationally Constrained Analogues of Epibatidine and Development of Non-opioidal Analgesics
| Project/Area Number |
12557203
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
KIBAYASHI Chihiko Tokyo University of Pharmacy and Life Science, School of Pharmacy, Professor, 薬学部, 教授 (80057330)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Hideki Tokyo University of Pharmacy and Life Science, School of Pharmacy, Assistant Professor, 薬学部, 助手 (00328551)
YAMAZAKI Naoki Tokyo University of Pharmacy and Life Science, School of Pharmacy, Assistant Professor, 薬学部, 講師 (30277264)
AOYAGI Sakae Tokyo University of Pharmacy and Life Science, School of Pharmacy, Associate Professor, 薬学部, 助教授 (30212385)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2001: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥3,700,000 (Direct Cost: ¥3,700,000)
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| Keywords | 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 |
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| Research Abstract |
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.
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Report
(3 results)
Research Products
(2 results)
