New 1,2,4-oxadiazole Derivatives with Positive MGlu Receptor Modulation Activity and Antipsychotic-like Properties

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2021 Dec 13

PMID 34894953

Citations 1

Authors

Anna Stankiewicz

Katarzyna Kaczorowska

Ryszard Bugno

Aneta Koziol

Maria H Paluchowska

Grzegorz Burnat

Barbara Chruscicka

Paulina Chorobik

Piotr Branski

Joanna M Wieronska

Beata Duszynska

Andrzej Pilc

Andrzej J Bojarski

Affiliations

Soon will be listed here.

Abstract

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu receptor positive allosteric modulatory activity (EC = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu, mGlu and mGlu receptors, but modulated mGlu and mGlu 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 PAM derivative (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 (, , , and ) 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 (), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu PAM ADX88178.

Citing Articles

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles.

Baykov S, Shetnev A, Semenov A, Baykova S, Boyarskiy V Int J Mol Sci. 2023; 24(6).

PMID: 36982481 PMC: 10056168. DOI: 10.3390/ijms24065406.

References

Niswender C, Lebois E, Luo Q, Kim K, Muchalski H, Yin H . Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators. Bioorg Med Chem Lett. 2008; 18(20):5626-30. PMC: 3182458. DOI: 10.1016/j.bmcl.2008.08.087. View

Hong S, Liu K, Ma G, Sabio M, Uberti M, Bacolod M . Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. J Med Chem. 2011; 54(14):5070-81. DOI: 10.1021/jm200290z. View

Xia G, You X, Liu L, Liu H, Wang J, Shi Y . Design, synthesis and SAR of piperidyl-oxadiazoles as 11β-hydroxysteroid dehydrogenase 1 inhibitors. Eur J Med Chem. 2013; 62:1-10. DOI: 10.1016/j.ejmech.2012.12.059. View

Kalinichev M, Le Poul E, Bolea C, Girard F, Campo B, Fonsi M . Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders. J Pharmacol Exp Ther. 2014; 350(3):495-505. PMC: 4152882. DOI: 10.1124/jpet.114.214437. View

Ngomba R, Ferraguti F, Badura A, Citraro R, Santolini I, Battaglia G . Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology. 2007; 54(2):344-54. DOI: 10.1016/j.neuropharm.2007.10.004. View

Spooren W, Schoeffter P, Gasparini F, Kuhn R, Gentsch C . Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608). Eur J Pharmacol. 2002; 435(2-3):161-70. DOI: 10.1016/s0014-2999(01)01562-x. View

Battaglia G, Busceti C, Molinaro G, Biagioni F, Traficante A, Nicoletti F . Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurosci. 2006; 26(27):7222-9. PMC: 6673941. DOI: 10.1523/JNEUROSCI.1595-06.2006. View

Charvin D, Di Paolo T, Bezard E, Gregoire L, Takano A, Duvey G . An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates. Mov Disord. 2018; 33(10):1619-1631. DOI: 10.1002/mds.27462. View

East S, Gerlach K . mGluR4 positive allosteric modulators with potential for the treatment of Parkinson's disease: WO09010455. Expert Opin Ther Pat. 2010; 20(3):441-5. DOI: 10.1517/13543770903551295. View

10.

Engers D, Field J, Le U, Zhou Y, Bolinger J, Zamorano R . Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats. J Med Chem. 2011; 54(4):1106-10. PMC: 3166797. DOI: 10.1021/jm101271s. View

11.

Chruscicka B, Burnat G, Branski P, Chorobik P, Lenda T, Marciniak M . Tetracycline-based system for controlled inducible expression of group III metabotropic glutamate receptors. J Biomol Screen. 2014; 20(3):350-8. DOI: 10.1177/1087057114559183. View

12.

Charvin D, Pomel V, Ortiz M, Frauli M, Scheffler S, Steinberg E . Discovery, Structure-Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4. J Med Chem. 2017; 60(20):8515-8537. DOI: 10.1021/acs.jmedchem.7b00991. View

13.

East S, Bamford S, Dietz M, Eickmeier C, Flegg A, Ferger B . An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction. Bioorg Med Chem Lett. 2010; 20(16):4901-5. DOI: 10.1016/j.bmcl.2010.06.078. View

14.

Bennouar K, Uberti M, Melon C, Bacolod M, Jimenez H, Cajina M . Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia. Neuropharmacology. 2012; 66:158-69. DOI: 10.1016/j.neuropharm.2012.03.022. View

15.

Harpsoe K, Isberg V, Tehan B, Weiss D, Arsova A, Marshall F . Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants. Sci Rep. 2015; 5:13869. PMC: 4566082. DOI: 10.1038/srep13869. View

16.

Stachowicz K, Klodzinska A, Palucha-Poniewiera A, Schann S, Neuville P, Pilc A . The group III mGlu receptor agonist ACPT-I exerts anxiolytic-like but not antidepressant-like effects, mediated by the serotonergic and GABA-ergic systems. Neuropharmacology. 2009; 57(3):227-34. DOI: 10.1016/j.neuropharm.2009.06.005. View

17.

Moghaddam B, Javitt D . From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2011; 37(1):4-15. PMC: 3238069. DOI: 10.1038/npp.2011.181. View

18.

Biernacki K, Dasko M, Ciupak O, Kubinski K, Rachon J, Demkowicz S . Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery. Pharmaceuticals (Basel). 2020; 13(6). PMC: 7345688. DOI: 10.3390/ph13060111. View

19.

Bedford C, Howd R, Dailey O, Miller A, Nolen 3rd H, Kenley R . Nonquaternary cholinesterase reactivators. 3. 3(5)-Substituted 1,2,4-oxadiazol-5(3)-aldoximes and 1,2,4-oxadiazole-5(3)-thiocarbohydroximates as reactivators of organophosphonate-inhibited eel and human acetylcholinesterase in vitro. J Med Chem. 1986; 29(11):2174-83. DOI: 10.1021/jm00161a008. View

20.

Jimenez H, Liu K, Hong S, Reitman M, Uberti M, Bacolod M . 4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators. Bioorg Med Chem Lett. 2012; 22(9):3235-9. DOI: 10.1016/j.bmcl.2012.03.032. View