MRK-016

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效的、功能选择性的、CNS 穿透性、口服生物可利用的 GABAA α5 受体苯二氮卓位点反向激动剂。

A potent, functionally selective, CNS-penetrating and orally bioavailable inverse agonist of benzodiazepine site of GABAA α5 receptor with Ki of 0.8-1.5 nM for α1-, α2-, α3-, andα5-containing GABAA receptors; has inverse agonist efficacy selective for the α5 subtype, increases long-term potentiation in mouse hippocampal slices; enhances performance in animal models of cognition, does not exhibit the convulsant, proconvulsant, or anxiogenic activity associated with nonselective GABAA inverse agonists.

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

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. 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. MRK-016 (3 mg/kg, i.p.) protects against LPS-induced learning/memory decrements in mice.

MRK016 | MRK 016

Membrane Transporter/Ion Channel

GAT

GAT

Cancer

——

342652-67-9

368.3931

C17H20N8O2

>98% (HPLC)

10 mM in DMSO

CC1=CC(=NO1)C2=NN=CC3=C(C(=NN32)OCC4=NC=NN4C)C(C)(C)C

Pyrazolo[1,5-d][1,2,4]triazine, 3-(1,1-dimethylethyl)-7-(5-methyl-3-isoxazolyl)-2-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-

(-20℃)

With Ice Pack

≥ 2 years