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. IC50 & Target: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] In Vitro: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 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]. In Vivo: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].