MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans
| Autor: | J. N. de Hoon, Guy Bormans, John R. Atack, M. G Murphy, Sandra M. Sanabria-Bohórquez, I De Lepeleire, A. Van Hecken, Keith A. Wafford, G. R. Dawson, K. Van Laere, Richard Hargreaves, Leslie J. Street, Ruth M. McKernan, Spencer J. Tye, HD Burns |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Agonist medicine.medical_specialty Adolescent Hydrocarbons Fluorinated medicine.drug_class Sedation Drug Evaluation Preclinical Anxiety Pharmacology Heterocyclic Compounds 4 or More Rings Anxiolytic Partial agonist Chlordiazepoxide Rats Sprague-Dawley Mice Young Adult Species Specificity Internal medicine medicine Animals Humans Tissue Distribution Pharmacology (medical) GABA-A Receptor Agonists Saimiri Benzodiazepine Binding Sites Dose-Response Relationship Drug Chemistry GABAA receptor Brain Middle Aged Rats Disease Models Animal Protein Subunits Psychiatry and Mental health Endocrinology Anti-Anxiety Agents Flumazenil Positron-Emission Tomography medicine.symptom Protein Binding medicine.drug |
| Zdroj: | Journal of Psychopharmacology. 25:314-328 |
| ISSN: | 1461-7285 0269-8811 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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