ADX88178
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MedKoo CAT#: 526673

CAS#: 1235318-89-4

Description: ADX-88178 is 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.

Chemical Structure

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ADX88178
CAS# 1235318-89-4
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 526673
Name: ADX88178
CAS#: 1235318-89-4
Chemical Formula: C12H12N6S
Exact Mass: 272.08
Molecular Weight: 272.330
Elemental Analysis: C, 52.93; H, 4.44; N, 30.86; S, 11.77

Price and Availability

Size Price Availability Quantity
100mg USD 950 2 Weeks
200mg USD 1650 2 Weeks
500mg USD 2450 2 Weeks
1g USD 3250 2 Weeks
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Synonym: ADX-88178; ADX 88178; ADX88178.

IUPAC/Chemical Name: 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine

InChi Key: MIQNXKWDQRNHAU-UHFFFAOYSA-N

InChi Code: InChI=1S/C12H12N6S/c1-7-3-4-13-11(16-7)18-12-17-10(8(2)19-12)9-5-14-15-6-9/h3-6H,1-2H3,(H,14,15)(H,13,16,17,18)

SMILES Code: CC1=NC(NC2=NC(C3=CNN=C3)=C(C)S2)=NC=C1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Product Data:
Product Data
Instruction:
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Biological target: ADX88178 is a metabotropic glutamate receptor 4 positive allosteric modulator (mGluR4 PAM) with an EC50 of 4 nM for human mGluR4.
In vitro activity: Pretreatment with ADX88178 caused a concentration-dependent reduction of nitrite levels, with 20 μM causing the most significant attenuation in NO levels (LPS vs. LPS+ADX88178 20 μM; P < 0.0001; Fig. 3A). There was a robust increase in TNF-α (control vs. LPS, P < 0.0001; Fig. 3B) and IL-1β (control vs. LPS, P < 0.001; Fig. 3C) protein levels after LPS stimulation, which were significantly reduced by ADX88178 (TNF-α: LPS vs. LPS+ADX88178, P < 0.0001; Fig. 3B, IL-1β: LPS vs. LPS+ADX88178, P < 0.05; Fig. 3C). The mRNA expression of pro-inflammatory cytokines (TNF-α and IL-1β), inflammatory microRNA (miR-155), as well as anti-inflammatory Arginase-1 were also evaluated. LPS stimulation significantly increased expression of TNF-α (control vs. LPS, P < 0.001; Fig. 3D), IL-1β (control vs. LPS, P < 0.01; Fig. 3E), and miR-155 (control vs. LPS, P < 0.0001; Fig. 3F). Similar to data obtained from BV2 microglia, ADX88178 reduced LPS-stimulated levels of the following inflammatory mediators in primary microglia: TNF-α (LPS vs. LPS+ADX88178, P < 0.01; Fig. 3D), IL-1β (LPS vs. LPS+ADX88178, P < 0.05; Fig. 3E), and miR-155 (LPS vs. LPS+ADX88178, P < 0.001; Fig. 3F). Reference: Neurochem Int. 2020 Sep;138:104770. https://pubmed.ncbi.nlm.nih.gov/32454165/
In vivo activity: To determine if activation of mGlu4 on microglial cells also leads to alterations in MHCII expression, microglia from WT and mGlu4 KO mice were pretreated for 45 min with ADX88178 and then stimulated with LPS for 24 h. Based on the potency of the ADX88178 compound in the TNF assay, this experiment was performed with 1 nM, 10 nM, and 100 nM ADX88178. The cells were then fixed and stained for immunocytochemical detection. MHCII expression was determined using confocal microscopy and quantified with ImageJ software. As shown in Fig. 2A, we found that LPS led to a marked enhancement of MHCII staining in WT microglia. There was a significant decrease (p < 0.001, one-way ANOVA with a Tukey’s post hoc test) in MHCII expression when microglia from WT mice were pretreated with ADX88178 prior to LPS stimulation. Similar pretreatment of microglia from mGlu4 KO mice showed that ADX88178 treatment did not alter MHCII expression in the KO cells (Fig. 2B), confirming the specificity of attenuation by ADX88178 through mGlu4. Reference: J Neuroimmune Pharmacol. 2016 Jun; 11(2): 231–237. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848139/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 16.7 61.21

Preparing Stock Solutions

The following data is based on the product molecular weight 272.33 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Abulwerdi G, Stoica BA, Loane DJ, Faden AI. Putative mGluR4 positive allosteric modulators activate Gi-independent anti-inflammatory mechanisms in microglia. Neurochem Int. 2020 Sep;138:104770. doi: 10.1016/j.neuint.2020.104770. Epub 2020 May 23. PMID: 32454165; PMCID: PMC7392812. 2. Volpi C, Mondanelli G, Pallotta MT, Vacca C, Iacono A, Gargaro M, Albini E, Bianchi R, Belladonna ML, Celanire S, Mordant C, Heroux M, Royer-Urios I, Schneider M, Vitte PA, Cacquevel M, Galibert L, Poli SM, Solari A, Bicciato S, Calvitti M, Antognelli C, Puccetti P, Orabona C, Fallarino F, Grohmann U. Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells. Neuropharmacology. 2016 Mar;102:59-71. doi: 10.1016/j.neuropharm.2015.10.036. Epub 2015 Oct 30. PMID: 26522434; PMCID: PMC4720030. 3. Ponnazhagan R, Harms AS, Thome AD, Jurkuvenaite A, Gogliotti R, Niswender CM, Conn PJ, Standaert DG. The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia. J Neuroimmune Pharmacol. 2016 Jun;11(2):231-7. doi: 10.1007/s11481-016-9655-z. Epub 2016 Feb 12. PMID: 26872456; PMCID: PMC4848139. 4. Kalinichev M, Le Poul E, Boléa C, Girard F, Campo B, Fonsi M, Royer-Urios I, Browne SE, Uslaner JM, Davis MJ, Raber J, Duvoisin R, Bate ST, Reynolds IJ, Poli S, Celanire S. 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 Sep;350(3):495-505. doi: 10.1124/jpet.114.214437. Epub 2014 Jun 19. PMID: 24947466; PMCID: PMC4152882.
In vitro protocol: 1. Abulwerdi G, Stoica BA, Loane DJ, Faden AI. Putative mGluR4 positive allosteric modulators activate Gi-independent anti-inflammatory mechanisms in microglia. Neurochem Int. 2020 Sep;138:104770. doi: 10.1016/j.neuint.2020.104770. Epub 2020 May 23. PMID: 32454165; PMCID: PMC7392812. 2. Volpi C, Mondanelli G, Pallotta MT, Vacca C, Iacono A, Gargaro M, Albini E, Bianchi R, Belladonna ML, Celanire S, Mordant C, Heroux M, Royer-Urios I, Schneider M, Vitte PA, Cacquevel M, Galibert L, Poli SM, Solari A, Bicciato S, Calvitti M, Antognelli C, Puccetti P, Orabona C, Fallarino F, Grohmann U. Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells. Neuropharmacology. 2016 Mar;102:59-71. doi: 10.1016/j.neuropharm.2015.10.036. Epub 2015 Oct 30. PMID: 26522434; PMCID: PMC4720030.
In vivo protocol: 1. Ponnazhagan R, Harms AS, Thome AD, Jurkuvenaite A, Gogliotti R, Niswender CM, Conn PJ, Standaert DG. The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia. J Neuroimmune Pharmacol. 2016 Jun;11(2):231-7. doi: 10.1007/s11481-016-9655-z. Epub 2016 Feb 12. PMID: 26872456; PMCID: PMC4848139. 2. Kalinichev M, Le Poul E, Boléa C, Girard F, Campo B, Fonsi M, Royer-Urios I, Browne SE, Uslaner JM, Davis MJ, Raber J, Duvoisin R, Bate ST, Reynolds IJ, Poli S, Celanire S. 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 Sep;350(3):495-505. doi: 10.1124/jpet.114.214437. Epub 2014 Jun 19. PMID: 24947466; PMCID: PMC4152882.

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1: Marszalek-Grabska M, Gibula-Bruzda E, Bodzon-Kulakowska A, Suder P, Gawel K, Talarek S, Listos J, Kedzierska E, Danysz W, Kotlinska JH. ADX-47273, a mGlu5 receptor positive allosteric modulator, attenuates deficits in cognitive flexibility induced by withdrawal from 'binge-like' ethanol exposure in rats. Behav Brain Res. 2018 Feb 15;338:9-16. doi: 10.1016/j.bbr.2017.10.007. Epub 2017 Oct 10. PMID: 29030082.


2: Engers DW, Rodriguez AL, Williams R, Hammond AS, Venable D, Oluwatola O, Sulikowski GA, Conn PJ, Lindsley CW. Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273. ChemMedChem. 2009 Apr;4(4):505-11. doi: 10.1002/cmdc.200800357. PMID: 19197923; PMCID: PMC2865690.


3: Lamb JP, Engers DW, Niswender CM, Rodriguez AL, Venable DF, Conn PJ, Lindsley CW. Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists. Bioorg Med Chem Lett. 2011 May 1;21(9):2711-4. doi: 10.1016/j.bmcl.2010.11.119. Epub 2010 Dec 3. PMID: 21183344; PMCID: PMC3179182.


4: Stauffer SR. Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). ACS Chem Neurosci. 2011 Aug 17;2(8):450-70. doi: 10.1021/cn2000519. Epub 2011 Jun 27. PMID: 22860171; PMCID: PMC3369763.


5: Kroker KS, Rast G, Rosenbrock H. Differential effect of the mGlu5 receptor positive allosteric modulator ADX-47273 on early and late hippocampal LTP. Neuropharmacology. 2011 Sep;61(4):707-14. doi: 10.1016/j.neuropharm.2011.05.014. Epub 2011 May 27. PMID: 21640734.


6: Rosenbrock H, Kramer G, Hobson S, Koros E, Grundl M, Grauert M, Reymann KG, Schröder UH. Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator. Eur J Pharmacol. 2010 Aug 10;639(1-3):40-6. doi: 10.1016/j.ejphar.2010.02.057. Epub 2010 Apr 2. PMID: 20371241.


7: Xu J, Zhu Y, Kraniotis S, He Q, Marshall JJ, Nomura T, Stauffer SR, Lindsley CW, Conn PJ, Contractor A. Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning. Learn Mem. 2013 Jul 18;20(8):438-45. doi: 10.1101/lm.031666.113. PMID: 23869026; PMCID: PMC3718201.


8: Isherwood SN, Robbins TW, Dalley JW, Pekcec A. Bidirectional variation in glutamate efflux in the medial prefrontal cortex induced by selective positive and negative allosteric mGluR5 modulators. J Neurochem. 2018 Apr;145(2):111-124. doi: 10.1111/jnc.14290. Epub 2018 Feb 12. PMID: 29315577; PMCID: PMC5972455.


9: Bikbaev A, Manahan-Vaughan D. Metabotropic glutamate receptor, mGlu5, regulates hippocampal synaptic plasticity and is required for tetanisation- triggered changes in theta and gamma oscillations. Neuropharmacology. 2017 Mar 15;115:20-29. doi: 10.1016/j.neuropharm.2016.06.004. Epub 2016 Jul 6. PMID: 27395786.


10: Makarewicz D, Słomka M, Danysz W, Łazarewicz JW. Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats. Folia Neuropathol. 2015;53(4):301-8. doi: 10.5114/fn.2015.56544. PMID: 26785364.


11: Isherwood SN, Pekcec A, Nicholson JR, Robbins TW, Dalley JW. Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism. Psychopharmacology (Berl). 2015 Sep;232(18):3327-44. doi: 10.1007/s00213-015-3984-0. Epub 2015 Jun 12. PMID: 26063678.


12: de Paulis T, Hemstapat K, Chen Y, Zhang Y, Saleh S, Alagille D, Baldwin RM, Tamagnan GD, Conn PJ. Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. J Med Chem. 2006 Jun 1;49(11):3332-44. doi: 10.1021/jm051252j. PMID: 16722652.


13: Bradley SJ, Watson JM, Challiss RA. Effects of positive allosteric modulators on single-cell oscillatory Ca2+ signaling initiated by the type 5 metabotropic glutamate receptor. Mol Pharmacol. 2009 Dec;76(6):1302-13. doi: 10.1124/mol.109.059170. Epub 2009 Sep 8. PMID: 19737913; PMCID: PMC2784724.


14: Schlumberger C, Pietraszek M, Gravius A, Danysz W. Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia. Pharmacol Biochem Behav. 2010 Mar;95(1):23-30. doi: 10.1016/j.pbb.2009.12.002. Epub 2009 Dec 5. PMID: 19995568.


15: Kjaerby C, Bundgaard C, Fejgin K, Kristiansen U, Dalby NO. Repeated potentiation of the metabotropic glutamate receptor 5 and the alpha 7 nicotinic acetylcholine receptor modulates behavioural and GABAergic deficits induced by early postnatal phencyclidine (PCP) treatment. Neuropharmacology. 2013 Sep;72:157-68. doi: 10.1016/j.neuropharm.2013.04.041. Epub 2013 May 2. PMID: 23643744.


16: Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, Atkinson PJ, Popiolek M, Wantuch C, Khawaja X, Smith D, Olsen M, Kouranova E, Lai M, Pruthi F, Pulicicchio C, Day M, Gilbert A, Pausch MH, Brandon NJ, Beyer CE, Comery TA, Logue S, Rosenzweig-Lipson S, Marquis KL. ADX47273 [S-(4-fluoro- phenyl)-{3-[3-(4-fluoro- phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. J Pharmacol Exp Ther. 2008 Dec;327(3):827-39. doi: 10.1124/jpet.108.136580. Epub 2008 Aug 27. PMID: 18753411.


17: Clifton NE, Morisot N, Girardon S, Millan MJ, Loiseau F. Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine. Psychopharmacology (Berl). 2013 Feb;225(3):579-94. doi: 10.1007/s00213-012-2845-3. Epub 2012 Sep 16. PMID: 22983144.


18: Schlumberger C, Pietraszek M, Gravius A, Klein KU, Greco S, Morè L, Danysz W. Comparison of the mGlu(5) receptor positive allosteric modulator ADX47273 and the mGlu(2/3) receptor agonist LY354740 in tests for antipsychotic-like activity. Eur J Pharmacol. 2009 Nov 25;623(1-3):73-83. doi: 10.1016/j.ejphar.2009.09.006. Epub 2009 Sep 16. PMID: 19765575.