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
Restricted accessResearch articleFirst published online March, 2011
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
MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant
GABAA 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
GABAA receptors, measured using an in vivo [3H]flumazenil binding assay,
with an Occ50 of 2.2 mg/kg p.o. and a corresponding plasma EC50
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
Cmax plasma concentration of 28 ng/mL, which, based on
the rodent plasma EC50 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 [11C]flumazenil uptake following a single dose of
1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of
GABAA 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.
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