MRK-409 (MK-0343) is a subtype-selective GABA(A) partial agonist that occupies the benzodiazepine site of GABA(A) receptors. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the alpha-1 subtype and significant efficacy at alpha -2 and alpha-3 subtypes of the GABA(A) receptor. MRK-409 binds to alpha-1, 2, 3 and 5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the alpha-3 compared with alpha-1 subtypes. MRK-409 exhibited anxiolytic and non-sedating properties in different rodent and primate models of unconditioned and conditioned models of anxiety but produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). It was suggested that the sedation with MRK-409 was due to the partial agonist efficacy of that compound at the alpha-1 subtype. Although MRK-409 (MK-0343) reached clinical studies its development had to be stopped due to sedative effects in humans demonstrated that more preclinical efforts are needed to identify compounds with improved selectivity.