WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 526625
CAS#: 783331-24-8
Description: MRK-016 is a selective α5 subunit-containing GABAA negative allosteric modulator that has nootropic properties. It has been found to produce rapid, ketamine-like antidepressant effects in animal models of depression.
MedKoo Cat#: 526625
Name: MRK-016
CAS#: 783331-24-8
Chemical Formula: C17H20N8O2
Exact Mass: 368.1709
Molecular Weight: 368.401
Elemental Analysis: C, 55.43; H, 5.47; N, 30.42; O, 8.69
Synonym: MRK-016; MRK 016; MRK016.
IUPAC/Chemical Name: 3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo(1,5-d)(1,2,4)triazine
InChi Key: QYSYOGCIDRANAR-UHFFFAOYSA-N
InChi Code: InChI=1S/C17H20N8O2/c1-10-6-11(23-27-10)15-21-19-7-12-14(17(2,3)4)16(22-25(12)15)26-8-13-18-9-20-24(13)5/h6-7,9H,8H2,1-5H3
SMILES Code: CN1N=CN=C1COC2=NN3C(C4=NOC(C)=C4)=NN=CC3=C2C(C)(C)C
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
| Biological target: | MRK-016 is a selective α5 subunit-containing GABAA negative allosteric modulator that has nootropic properties. |
| In vitro activity: | In vitro activity This study quantified the effects of four α5-specific inverse agonists (TB-21007, MRK-016, α5IA and L-655708) on IPSCs (inhibitory postsynaptic currents) mediated by the three isoforms. All compounds selectively inhibited IPSC amplitudes and accelerated IPSC decay rates, albeit with distinct isoform specificities. MRK-016 also significantly accelerated IPSC rise times. Reference: Neuropharmacology. 2017 Oct;125:243-253. https://pubmed.ncbi.nlm.nih.gov/28757051/ |
| In vivo activity: | A peripheral injection of the GABA-NAM MRK-016 restored hedonic behavior and AMPA-to-NMDA ratios in wild-type mice. MRK-016 administration increased gamma power over the prefrontal cortex in wild-type mice but not α5 knockout mice, whereas ketamine promoted gamma power in both genotypes. Hedonic behavior and AMPA-to-NMDA ratios were only restored by MRK-016 in stressed wild-type mice but not α5 knockout mice. Reference: Biol Psychiatry. 2022 Aug 1;92(3):216-226. https://pubmed.ncbi.nlm.nih.gov/35120711/ |
The following data is based on the product molecular weight 368.401 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.
| 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. Chen X, Keramidas A, Lynch JW. Physiological and pharmacological properties of inhibitory postsynaptic currents mediated by α5β1γ2, α5β2γ2 and α5β3γ2 GABAA receptors. Neuropharmacology. 2017 Oct;125:243-253. doi: 10.1016/j.neuropharm.2017.07.027. Epub 2017 Jul 27. PMID: 28757051. 2. Troppoli TA, Zanos P, Georgiou P, Gould TD, Rudolph U, Thompson SM. Negative Allosteric Modulation of Gamma-Aminobutyric Acid A Receptors at α5 Subunit-Containing Benzodiazepine Sites Reverses Stress-Induced Anhedonia and Weakened Synaptic Function in Mice. Biol Psychiatry. 2022 Aug 1;92(3):216-226. doi: 10.1016/j.biopsych.2021.11.024. Epub 2021 Dec 15. PMID: 35120711; PMCID: PMC9198111. 3. Paine TA, Chang S, Poyle R. Contribution of GABAA receptor subunits to attention and social behavior. Behav Brain Res. 2020 Jan 27;378:112261. doi: 10.1016/j.bbr.2019.112261. Epub 2019 Sep 24. PMID: 31560920; PMCID: PMC6948928. |
| In vitro protocol: | 1. Chen X, Keramidas A, Lynch JW. Physiological and pharmacological properties of inhibitory postsynaptic currents mediated by α5β1γ2, α5β2γ2 and α5β3γ2 GABAA receptors. Neuropharmacology. 2017 Oct;125:243-253. doi: 10.1016/j.neuropharm.2017.07.027. Epub 2017 Jul 27. PMID: 28757051. |
| In vivo protocol: | 1. Troppoli TA, Zanos P, Georgiou P, Gould TD, Rudolph U, Thompson SM. Negative Allosteric Modulation of Gamma-Aminobutyric Acid A Receptors at α5 Subunit-Containing Benzodiazepine Sites Reverses Stress-Induced Anhedonia and Weakened Synaptic Function in Mice. Biol Psychiatry. 2022 Aug 1;92(3):216-226. doi: 10.1016/j.biopsych.2021.11.024. Epub 2021 Dec 15. PMID: 35120711; PMCID: PMC9198111. 2. Paine TA, Chang S, Poyle R. Contribution of GABAA receptor subunits to attention and social behavior. Behav Brain Res. 2020 Jan 27;378:112261. doi: 10.1016/j.bbr.2019.112261. Epub 2019 Sep 24. PMID: 31560920; PMCID: PMC6948928. |
1: Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM. Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors. Neuropsychopharmacology. 2015 Oct;40(11):2499-509. doi: 10.1038/npp.2015.112. Epub 2015 Apr 22. PubMed PMID: 25900119; PubMed Central PMCID: PMC4569955.
2: Eimerbrink MJ, White JD, Pendry RJ, Hodges SL, Sadler LN, Wiles JD, Weintraub MK, Chumley MJ, Boehm GW. Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin. Behav Brain Res. 2015 Jul 15;288:50-3. doi: 10.1016/j.bbr.2015.03.048. Epub 2015 Mar 28. PubMed PMID: 25823763.
3: Lecker I, Yin Y, Wang DS, Orser BA. Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists. Br J Anaesth. 2013 Jun;110 Suppl 1:i73-81. doi: 10.1093/bja/aet038. Epub 2013 Mar 27. PubMed PMID: 23535829; PubMed Central PMCID: PMC3732063.
4: Atack JR. GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement. Curr Top Med Chem. 2011;11(9):1203-14. Review. PubMed PMID: 21050171.
5: Atack JR, Maubach KA, Wafford KA, O'Connor D, Rodrigues AD, Evans DC, Tattersall FD, Chambers MS, MacLeod AM, Eng WS, Ryan C, Hostetler E, Sanabria SM, Gibson RE, Krause S, Burns HD, Hargreaves RJ, Agrawal NG, McKernan RM, Murphy MG, Gingrich K, Dawson GR, Musson DG, Petty KJ. In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)- pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist. J Pharmacol Exp Ther. 2009 Nov;331(2):470-84. doi: 10.1124/jpet.109.157636. Epub 2009 Aug 24. PubMed PMID: 19704033.
6: Jones P, Atack JR, Braun MP, Cato BP, Chambers MS, O'Connor D, Cook SM, Hobbs SC, Maxey R, Szekeres HJ, Szeto N, Wafford KA, MacLeod AM. Pharmacokinetics and metabolism studies on (3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy) pyrazolo[1,5-d][1,2,4]triazine, a functionally selective GABA(A) alpha5 inverse agonist for cognitive dysfunction. Bioorg Med Chem Lett. 2006 Feb 15;16(4):872-5. Epub 2005 Nov 21. PubMed PMID: 16303300.
7: Chambers MS, Atack JR, Carling RW, Collinson N, Cook SM, Dawson GR, Ferris P, Hobbs SC, O'connor D, Marshall G, Rycroft W, Macleod AM. An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties. J Med Chem. 2004 Nov 18;47(24):5829-32. PubMed PMID: 15537339.
