New 1,2,4-oxadiazole derivatives with positive mGlu
| Autor: | Anna, Stankiewicz, Katarzyna, Kaczorowska, Ryszard, Bugno, Aneta, Kozioł, Maria H, Paluchowska, Grzegorz, Burnat, Barbara, Chruścicka, Paulina, Chorobik, Piotr, Brański, Joanna M, Wierońska, Beata, Duszyńska, Andrzej, Pilc, Andrzej J, Bojarski |
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| Rok vydání: | 2021 |
| Předmět: |
anxiolytics
Oxadiazoles Dose-Response Relationship Drug Molecular Structure 1 2 4-oxadiazoles Receptors Metabotropic Glutamate Metabotropic glutamate receptor 4 (mGlu4 receptor) Mice Structure-Activity Relationship antipsychotic properties Allosteric Regulation Animals positive allosteric modulator (PAM) Antipsychotic Agents Research Article Research Paper |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry article-version (VoR) Version of Record |
| ISSN: | 1475-6374 |
| Popis: | Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu4 receptor positive allosteric modulatory activity (EC50 = 282–656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1, mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM ADX88178. Graphical Abstract |
| Databáze: | OpenAIRE |
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