Preclinical and clinical pharmacology of TPA023B, a GABA_A receptor α2/α3 subtype-selective partial agonist

Abstract

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Benzodiazepine Binding Site Occupancy by the Novel GABAA 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

“…Likewise, the structurally related compound ␣51A was also more potent in humans compared with preclinical species (respective EC 50 values of 10 ng/ml versus 52-57 ng/ml) (Atack et al, 2009a) as was the imidazotriazine TPA023B (EC 50 values of 19, 10, and 5.8 ng/ml in rats, baboons, and humans, respectively) (Atack et al, 2009b). In contrast, lorazepam seems to have a similar potency in rats and humans, albeit that the low levels of occupancy achieved in humans limit the reliability of such a comparison.…”

“…These data are consistent with the lack of efficacy of TPA023 at ␣1-containing receptors, the subtype of GABA A receptor responsible for the sedative effects of diazepam (Rudolph et al, 1999;McKernan et al, 2000) and are in agreement with the pharmacodynamic effects of TPA023, which showed that doses of 0.5 and 1.5 mg did not produce the sedation-like effects (e.g., increased body sway, decreased alertness measured using a visual analog scale) observed with lorazepam (de Haas et al, 2007). Similarly, data with the ␣2/␣3-selective compound TPA023B, which is an imidazotriazine follow-up compound to TPA023, showed that levels of occupancy in the region of 50% could be achieved in the absence of overt sedation (Van Laere et al, 2008;Atack et al, 2009b). However, in contrast to the relatively high levels of occupancy achieved in human TPA023 and TPA023B in the absence of overt sedation, MRK-409 (also known as MK-0343) (de Haas et al, 2008), produced sedation and somnolence at doses of 1.5 and 2 mg, with occupancy at the maximal tolerated dose of 1 mg being below the levels of detection (Յ10%) (Atack et al, 2009c).…”

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

“…Preclinical studies with rodents and efficacy-selective BDZ-site compounds have usually yielded results that are in accordance with the behavioral effects mediated by GABA A R ␣1/␣2/␣3/␣5 subtypes. However, compound 7-cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,6-difluorophenyl)-1,2,4-triazolo [4,3-b]pyridazine (MRK-409), which has selective efficacy at ␣2/␣3-over ␣1-containing GABA A Rs and produces minimal signs of sedation in rodents at receptor occupancies over 90%, has sedative effects in humans at relatively low occupancy (Atack et al, 2010). This sedation might be due to the partial agonist efficacy of the compound at the ␣1 subtype (Atack et al, 2010).…”

“…However, compound 7-cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,6-difluorophenyl)-1,2,4-triazolo [4,3-b]pyridazine (MRK-409), which has selective efficacy at ␣2/␣3-over ␣1-containing GABA A Rs and produces minimal signs of sedation in rodents at receptor occupancies over 90%, has sedative effects in humans at relatively low occupancy (Atack et al, 2010). This sedation might be due to the partial agonist efficacy of the compound at the ␣1 subtype (Atack et al, 2010). Furthermore, humans are obviously more sensitive and aware of the sedative effects of a drug than are the species used in preclinical studies (Whiting, 2006).…”

Involvement of Histaminergic System in the Anxiolytic-Like Activities of <i>Morus alba</i> Leaves in Mice

“…Neither flumazenil nor WAY-100635 showed any changes in the percentage of entries into open arms and the percentage of time spent in the open arms, as shown in the previous reports. 14,27) With the administration of flumazenil, the increases of the percentages of entries into open arms and time spent in the open arms were not changed compared with those of EMA treatment. Moreover, the similar results were also obtained with the treatment of WAY-100635.…”