MRK-016 

MRK-016 is a selective, orally bioavailable inverse agonist of GABA_A α5 receptor, with an EC₅₀ of 3 nM for GABA_A α5, and K_is of 0.83, 0.85, 0.77 and 1.4 nM for human GABA_A α1β3γ2, GABA_A α2β3γ2, GABA_A α3β3γ2, and GABA_A α5β3γ2, respectively; MRK-016 also readily penetrates the CNS.

EC50: 3 nM (GABA_A α5)^[1]
Ki: 0.83 nM (Human GABA_A α1β3γ2), 0.85 nM (Human GABA_A α2β3γ2), 0.77 nM (Human GABA_A α3β3γ2), 1.4 nM (Human GABA_A α5β3γ2)^[1]

MRK-016 is a selective, orally bioavailable inverse agonist of GABA_A α5 receptor, with an EC₅₀ of 3 nM for GABA_A α5, and K_is of 0.83, 0.85, 0.77 and 1.4 nM for human GABA_A α1β3γ2, GABA_A α2β3γ2, GABA_A α3β3γ2, and GABA_A α5β3γ2, respectively^[1][2]. MRK-016 is a full inverse agonist at the α5-subtype, shows very weak affinity at the GABA_A α4β3γ2-subtype (K_i 395 ± 173 nM) and is essentially inactive at the GABA_A α6β3γ2 receptor (K_i > 4000 nM)^[1]. MRK-016 shows a weak effect on GABA_A α4β3γ2 with a K_i of 400 nM. MRK-016 (100 nM) alao increases long-term potentiation in mouse hippocampal slices^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

MRK-016 does not enhance pentylenetetrazole-induced convulsions at 10 mg/kg via ip, or cause seizures at 30 mg/kg, via po for 20 days in mice. MRK-016 shows no obvious anxiogenic-like effects in rats at doses that occupy >95% of benzodiazepine (BZ) binding sites. MRK-016 (0.3, 1, and 3 mg/kg, p.o.) dose-dependently improves performance of rats hippocampal-dependent memory task^[1]. MRK-016 (0.3-30 mg/kg, p.o.) causes good receptor occupancy in rats. MRK-016 (0.3, 1, or 3 mg/kg p.o.) shows cognition-enhancing activity in the delayed matching-to-position version of the Morris water maze. MRK-016 (1, 3, or 10 mg/kg i.p.) does not produce kindling in mice^[2]. MRK-016 (3 mg/kg, i.p.) protects against LPS-induced learning/memory decrements in mice^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

368.39

Solid

C₁₇H₂₀N₈O₂

342652-67-9

CN1N=CN=C1COC2=NN3C(C4=NOC(C)=C4)=NN=CC3=C2C(C)(C)C

Room temperature in continental US; may vary elsewhere.

• [1]. Chambers MS, et al. 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.  [Content Brief]

  [2]. Atack JR, et al. 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.  [Content Brief]

  [3]. Eimerbrink MJ, et al. 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.  [Content Brief]