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

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu ₄ receptor positive allosteric modulatory activity (EC ₅₀ = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu ₁ , mGlu ₂ and mGlu ₅ receptors, but modulated mGlu ₇ and mGlu ₈ 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 mGlu ₄ 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 mGlu ₄ PAM ADX88178.