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

Abstract

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

Keywords:

• Metabotropic glutamate receptor 4 (mGlu₄ receptor)
• positive allosteric modulator (PAM)
• 1,2,4-oxadiazoles
• antipsychotic properties
• anxiolytics

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the grant UDA-POIG.01.03.010–12-100/08 (ModAll) co-financed by European Union from the European Fund of Regional Development (EFRD), as well as by the statutory funding from the Maj Institute of Pharmacology, Polish Academy of Sciences, Poland.