New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties

• Main Authors: Anna Stankiewicz (Author), Katarzyna Kaczorowska (Author), Ryszard Bugno (Author), Aneta Kozioł (Author), Maria H. Paluchowska (Author), Grzegorz Burnat (Author), Barbara Chruścicka (Author), Paulina Chorobik (Author), Piotr Brański (Author), Joanna M. Wierońska (Author), Beata Duszyńska (Author), Andrzej Pilc (Author), Andrzej J. Bojarski (Author)
• Format: Book
• Published: Taylor & Francis Group, 2022-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

1475-6366
1475-6374
10.1080/14756366.2021.1998022