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

• Published in: Journal of psychopharmacology (Oxford) 2011-03, Vol.25 (3), p.314
• Main Authors: Atack, JR, Wafford, KA, Street, LJ, Dawson, GR, Tye, S, Van Laere, K, Bormans, G, Sanabria-Bohórquez, SM, De Lepeleire, I, de Hoon, JN, Van Hecken, A, Burns, HD, McKernan, RM, Murphy, MG, Hargreaves, RJ
• Format: Article
• Language: English
• Subjects: Binding sites; Mental disorders; Plasma; Proteins; Psychopharmacology; Tomography
• ISSN: 0269-8811; 1461-7285

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.