MRK-409 (MK-0343), a GABA_A receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans

Abstract

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

Benzodiazepine Binding Site Occupancy by the Novel GABAA Receptor Subtype-Selective Drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in Rats, Primates, and Humans

“…However, in contrast to the relatively high levels of occupancy achieved in human TPA023 and TPA023B in the absence of overt sedation, MRK-409 (also known as MK-0343) (de Haas et al, 2008), produced sedation and somnolence at doses of 1.5 and 2 mg, with occupancy at the maximal tolerated dose of 1 mg being below the levels of detection (Յ10%) (Atack et al, 2009c). The sedation produced by MRK-409 was attributed to the weak partial agonist efficacy that this compound had at the ␣1 subtype and clearly demonstrates the value of the measurement of receptor occupancy in interpreting clinical data (Atack et al, 2009c).…”

Antihyperalgesic Effect of the GABAA Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic–Pharmacodynamic Study

“…However, the development of MRK-409 was terminated because, unlike in pre-clinical tests, it failed to exhibit anxiolytic activity at non-sedative doses [28].…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…(37) also known as MK-0343 was originally designed to be a less sedating anxiolytic, based on reduced efficacy at the 1 subtype and significant efficacy at 2 and 3 subtypes of the GABA A receptor. The anxiolyticlike and sedative activity was observed at minimum effective doses corresponding to occupancies, depending on the model used, ranging from about 35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90% [360]. MK-0343 at 0.75 mg in humans was equipotent with lorazepam, on the other hand diminished effects on memory and postural stability were observed.…”