title: Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders.
abstract: There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.) mial@lundbeck.com sonia-maria.poli@addexpharma.com.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Le Poul
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Christelle
authors.initials: C
authors.lastname: Boléa
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Françoise
authors.initials: F
authors.lastname: Girard
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fonsi
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Royer-Urios
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Susan E
authors.initials: SE
authors.lastname: Browne
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Davis
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Robert
authors.initials: R
authors.lastname: Duvoisin
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Simon T
authors.initials: ST
authors.lastname: Bate
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Reynolds
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.) mial@lundbeck.com sonia-maria.poli@addexpharma.com.
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
authors.affiliation: Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland (M.K., E.L.P., C.B., F.G., B.C., M.F., I.R.-U., S.P., S.C.); Merck Research Laboratories, West Point, Pennsylvania (S.E.B., J.M.U., M.J.D., I.J.R.); Oregon Health & Science University, Portland, Oregon (M.J.D., J.R., R.D.); and Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Huntingdon, United Kingdom (S.T.B.).
authors.forename: Sylvain
authors.initials: S
authors.lastname: Celanire
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000502:physiology / Q000627:therapeutic use*; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: C000591920:5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine; D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C108823:metabotropic glutamate receptor 4