Research Article: An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

Date Published: January 29, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Xia Chen, Sanne de Haas, Marieke de Kam, Joop van Gerven.


Various α2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several α2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three α2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498), one α1-selective GABAA agonists (zolpidem), and another full agonist (alprazolam) were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV-) relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD). SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the α2,3 selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the α2,3-selective GABA-A agonists, implying an improved therapeutic window.

Partial Text

Anxiety is a psychological and physiological state with somatic, emotional, cognitive, and behavioral components [1], which dominates thinking and leads to disturbance of daily functioning. Serotonergic antidepressants, either selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), are currently prescribed as the 1st-line treatment for several anxiety disorders. However, the slow onset of therapeutic effect and the presence of sexual side effects prevent these drugs from more extensive use and lead to lack of treatment compliance [2]. Moreover, SSRIs/SNRIs cause transient increase of anxiety during the first few weeks of administration. All these clinical experiences provide space for the use of benzodiazepines (BZDs) in acute anxiety episodes.

Five clinical studies, all of which are published [12–15, 17], were conducted at the CHDR in healthy volunteers after approval from the Ethics Review Board of Leiden University Medical Centre. All subjects provided written inform consent for study participation. Each trial was designed as single-dose, cross-over or parallel-armed, randomized, double-blind, placebo- and/or positive-controlled study. The subjects took single oral doses of a selective GABAergic compound, placebo-, and/or a nonselective benzodiazepine. Three studies used lorazepam 2 mg as a positive control, whereas in the studies with zolpidem 10 mg and alprazolam 1 mg, these drugs were the only GABAergic study medications. Data of all studies came from the same research center and were pooled from the studies-specific electronic databases kept by the center. In vitro pharmacological parameters of novel compounds were extracted from the Investigator’s Brochures and published articles. These parameters provide reliable information about the subtype selectivity of each compound, but it is more difficult to compare the pharmacological properties between the drugs. Due to the diversity of cell types and GABAA receptor homologies used in the whole-cell patch clamping assays, the links between in vitro pharmacology and human in vivo effects are considered less quantitative and semiquantitative comparisons are preferred.

This analysis was performed to explore the central nervous system (CNS) effects of various GABAergic agents and characterize the pharmacodynamic effect profiles of these compounds in healthy volunteers and correlate such profiles to their pharmacological properties.

TPA023, TPACMP2, and SL65.1498 are members of the novel experimental drug family of α2,3-subtype selective receptor agonists. In vitro pharmacological properties of these compounds indicate higher binding affinity and relative efficacy at the α2,3-subunits. In vivo preclinical studies with animal models translated such pharmacological properties into potential of anxiolysis and relatively reduced off-target effects in comparison with nonselective full GABAergic agonists like benzodiazepines.




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