Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA_A α_2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers

Abstract

TPA023, a GABA(A) alpha2,3 alphasubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the alpha1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazepam 2 mg (therapeutic anxiolytic dose). Twelve healthy male volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on posturaL stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of lorazepam. In contrast to lorazepam, TPA023 had no detectabLe effects on saccadic latency or inaccuracy. Also unlike lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazepam, at doses that were equipotent with regard to effects on saccadic peak veLocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABA(A) receptor subtypes.

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

“…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).…”

“…Hence, the affinity of TPA023 for the different subtypes of GABA A receptors ranges from 0.2 to 0.4 nM, whereas SL65.1498 has affinity at the ␣1, ␣2, and ␣3 subtypes, ranging from 17 to 80 nM, with even lower affinity (215 nM) at the ␣5 subtype (Griebel et al, 2001). The C max values for the 0.5-and 1.5-mg doses of TPA023 were 5 and 13 ng/ml, respectively (de Haas et al, 2007), whereas respective values for the 2.5-, 7.5-, and 25-mg doses of SL65.1498 were 37, 126, and 375 ng/ml, respectively (de Haas et al, 2009). Accordingly, the plasma drug concentrations required for effects on saccadic eye movement peak velocity for TPA023 and SL-65.1498 were 5 and 375 ng/ml, respectively, again emphasizing the relative potency of TPA023.…”

“…The high affinity of TPA023 also presumably accounts for why effects of TPA023 on saccadic eye movement peak velocity were seen at doses of 0.5 and 1.5 mg (de Haas et al, 2007) that were an order of magnitude less than the minimally effective dose of 25 mg required for the lower affinity, ␣2/␣3-preferring compound SL65.1498 (de Haas et al, 2009). Hence, the affinity of TPA023 for the different subtypes of GABA A receptors ranges from 0.2 to 0.4 nM, whereas SL65.1498 has affinity at the ␣1, ␣2, and ␣3 subtypes, ranging from 17 to 80 nM, with even lower affinity (215 nM) at the ␣5 subtype (Griebel et al, 2001).…”

“…The maximal plasma concentrations of lorazepam after a single, 2-mg dose are in the region of 20 ng/ml (Greenblatt et al, 1988;de Haas et al, 2007), and a similar estimated concentration of TPA023, ϳ20 ng/ml, is achieved after a 2-mg dose of TPA023 (calculated by extrapolating from plasma pharmacokinetics of single doses of 0.5 and 1.5 mg of TPA023 (respective C max values ϭ ϳ5 and ϳ15 ng/ml) (de Haas et al, 2007). However, despite 2-mg doses of TPA023 and lorazepam achieving comparable plasma concentrations (20 ng/ml), TPA023 gave much higher levels of occupancy in humans compared with lorazepam (50 -60% versus Ͻ10%).…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…Finally, TPA-023 showed anticonvulsant activity in a mouse pentylenetetrazole seizure model [370]. TPA-023 had significant dose dependent effects on saccadic peak velocity that approximated the effects of lorazepam [371]. However in contrast to lorazepam, TPA-023 had no detectable effects on saccadic latency or inaccu-racy.…”