2004 Fiscal Year Final Research Report Summary
Development of histamine H_3 receptor selective ligands based on the versatile chiral cyclopropane units.
| Project/Area Number |
15590096
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
SHUTO Satoshi Hokkaido Univ., Grad.School of Pharm.Sci., Prof., 大学院・薬学研究科, 教授 (70241346)
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| Project Period (FY) |
2003 – 2004
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| Keywords | agonist / antagonist / conformationally restricted analogue / cyclopropane / drug design / histamine / H_3 receptor / H_1 receptor |
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| Research Abstract |
Highly selective H_3 agonists and also antagonists would not only be very useful as tools for pharmacological studies but would also be important as leads for the development of new drugs. We designed a series of cyclopropane-based conformationally restricted analogues of histamine, which were effectively synthesized from chiral cyclopropane units previously developed by us. Among these conformationally restricted analogues, (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane having the cis-cyclopropane structure was identified as a highly H_3-selective agonist. On the basis of these findings, cyclopropane-based H_3 selective antagonists were designed. These were designed by introducing an aromatic ring into the structure of the H_3 selective agonists found, since introduction of aromatic rings into the proper site of an agonist sometimes convert it into the corresponding antagonist, which has been recognized as "umbrella effect". These compounds were also synthesized from above chiral cyclopropane units, and some very strong H_3 receptor antagonists with selectivity were found. Thus, we successfully developed H_3 selective agonists and antagonists based on theoretical design using the versatile chiral cyclopropane units.
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