Benzodiazepine Binding Site Occupancy by the Novel GABA_A 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

Abstract

The GABA A receptor ␣2/␣3 subtype-selective compound 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; also known as MK-0777) is a triazolopyridazine that has similar, subnanomolar affinity for the benzodiazepine binding site of ␣1-, ␣2-, ␣3-, and ␣5-containing GABA A receptors and has partial agonist efficacy at the ␣2 and ␣3 but not the ␣1 or ␣5 subtypes. The purpose of the present study was to define the relationship between plasma TPA023 concentrations and benzodiazepine binding site occupancy across species measured using various methods. Thus, occupancy was measured using either in vivo 11 C]flumazenil PET in baboons and humans. For each study, plasma-occupancy curves were derived, and the plasma concentration of TPA023 required to produce 50% occupancy (EC 50 ) was calculated. The EC 50 values for rats, rhesus monkeys, and baboons were all similar and ranged from 19 to 30 ng/ml, although in humans, the EC 50 was slightly lower at 9 ng/ml. In humans, a single 2-mg dose of TPA023 produced in the region of 50 to 60% occupancy in the absence of overt sedative-like effects. Considering that nonselective full agonists are associated with sedation at occupancies of less than 30%, these data emphasize the relatively nonsedating nature of TPA023.The GABA A receptor is a pentameric assembly of subunits derived from a family of genes of which there are 19 members (␣1-6, ␤1-3, ␥1-3, ␦, ε, , , and 1-3), with the predominant composition of native receptors being ␣, ␤, and ␥ subunits, in a 2:2:1 stoichiometry and an ␣␤␣␤␥ arrangement as viewed from the synapse (Sieghart and Sperk, 2002

A Comparison of the 2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain

“…In order to fully interpret and compare the data generated with the two compounds used, we first determined the brain GABA A receptor occupancy of both L-838,417 and TPA023 and correlated this to nonprotein bound plasma drug levels (Figure 1). In terms of Occ50 values, TPA023 was approximately 0.3 mg/kg and L-838,417 was approximately 1 mg/kg, these data are very similar to those published by Merck [21, 22]. However, as equivalent doses did not always result in equivalent plasma exposures, in subsequent studies plasma samples were always taken for PK analysis and drug levels correlated to brain GABA A    receptor RO values determined from the results described above.…”

New Prospects for the Drug Treatment of Generalized Anxiety Disorder — A Systematic Review

“…MK-0777 is a GABA-A α2/α3 partial agonist, with little activity at α1 and α5 subunits, and was developed as a possible treatment for GAD devoid of anxiolytic or amnestic effects. No anxiolytic data from patients with GAD have been published, however a recent PET study in healthy volunteers reported that MK-0777 2mg produced 50-60% occupancy of central benzodiazepine receptors, without producing sedative effects [37]. Given that nonselective full agonist benzodiazepines produce sedation at <30% occupancy, these findings are consistent with a potentially improved tolerability profile for α2/α3 subtype selective ligands.…”

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

“…In contrast, at anxiolytic doses of non-selective positive allosteric modulators acting at the BZ site (diazepam, clonazepam, alprazolam, midazolam, lorazepam), significant drowsiness has been associated with low receptor occupancy, ranging from 2 to 30% (Shinotoh et al 1989; Pauli et al 1991; Sybirska et al 1993; Malizia et al 1996; Lingford-Hudges et al 2005). More recently, for the partial GABA A receptor agonists MRK-409 and TPA023, sedation has been reported at a broad range of receptor occupancy, from severe sedation at <10% occupancy (MRK-409) or lack of overt sedation up to 50% receptor occupancy (TPA023) (Atack et al 2010, 2011a,b). One possible explanation for this broad range of tolerated levels of GABA A receptor occupancy of novel partial GABA A receptor agonists may be their intrinsic activity as suggested in the early studies comparing GABA A receptor modulators (Bottlaender et al 1994).…”