Cyclopropane-Based Conformational Restriction of Histamine. (1S,2S)-2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a Highly Selective Agonist for the Histamine H3 Receptor, Having a cis-Cyclopropane Structure
| Autor: | and Akira Matsuda, Kentaro Natsume, Kazufumi Hirano, Kiyoshi Furuichi, § Shun-ichiro Matsumoto, Ryohei Kimura, Shizuo Yamada, Satoshi Shuto, Yuji Kazuta |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Cyclopropanes
Male Agonist Stereochemistry medicine.drug_class Molecular Conformation Stereoisomerism CHO Cells In Vitro Techniques Chemical synthesis Cyclopropane Histamine Agonists Rats Sprague-Dawley Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Cricetinae Drug Discovery medicine Animals Humans Receptors Histamine H3 Chemistry Imidazoles Diastereomer Brain Rats Molecular Medicine Enantiomer Histamine H3 receptor Histamine |
| Zdroj: | Journal of Medicinal Chemistry. 46:1980-1988 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor. |
| Databáze: | OpenAIRE |
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