| Autor: |
Dominguez C; Discovery Chemistry and Neuroscience Research Divisions, Eli Lilly and Company, Indianapolis, Indiana 46285, USA., Prieto L, Valli MJ, Massey SM, Bures M, Wright RA, Johnson BG, Andis SL, Kingston A, Schoepp DD, Monn JA |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2005 May 19; Vol. 48 (10), pp. 3605-12. |
| DOI: |
10.1021/jm040222y |
| Abstrakt: |
LY354740 (1) is a highly potent and selective agonist of metabotropic glutamate (mGlu) receptors 2 and 3. In the present study, we have prepared C3- and C4-methyl-substituted variants of rac-1, compounds 5, 9, and 13. Each of these racemic methyl-substituted analogues displaced specific binding of the mGlu2/3 receptor antagonist (3)H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid ((3)H-LY341495) from membranes expressing mGlu2 or mGlu3 receptor subtypes. Evaluation of the functional effects of this series on second messenger responses in cells expressing human mGlu2 or mGlu3 receptors revealed C3beta-methyl analogue 5 to possess antagonist properties at both mGlu2 and mGlu3 receptors while C4beta-methyl analogue 9 acts as a full agonist at each of these targets. Unexpectedly, we found that incorporation of a methyl substituent at the C4alpha-position as in analogue 13 results in a mixed mGlu2 agonist/mGlu3 antagonist pharmacological profile. All of the mGlu2 agonist and mGlu3 antagonist activity of rac-13 was found to reside in its resolved (+)-isomer. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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