Alzheimer’s Therapy: GABA Receptor Inverse Agonists

By | April 15, 2015

Overview. Benzodiazepine (BZD) drugs increase the inhibitory effects of gamma-aminobutyric acid (GABA) interneurons on cholinergic neurons. However, BZD drugs that function as antagonists, or inverse agonists, at receptor sites could have an excitatory effect on cholinergic neurons, thereby increasing levels of cholinergic activity and thus reducing the effects of neuronal loss in Alzheimer’s disease patients. This effect has prompted investigation into this class of agents as potential treatments for cognitive disorders, including Alzheimer’s disease. In addition to Shionogi/GlaxoSmithKline’s S-8510, which is furthest in development, there are several drugs currently in early-stage development for Alzheimer’s disease, including Aven-tis/Dainippon’s AC-3933, which initiated Phase II trials in Europe in November 2003.

Mechanism of Action. BZD drugs increase the inhibitory effects of GABA interneurons on cholinergic neurons. Drugs in this class that function as antagonists or inverse agonists at the GABA-A receptor sites (a subtype of GABA receptor) have an inverse effect on the cholinergic system and would theoretically increase cholinergic activity — a potential therapeutic intervention for Alzheimer’s disease that would delay the cognitive and functional decline associated with the disease. BZD drugs bind to sites on the GABA-A receptors in the CNS. Here, they modulate the gating action of GABA that controls the flow of chloride ions (Cl) through channels in neuronal membranes. By enhancing the effects of GABA on GABA receptors, BZD drugs increase the net influx of Cl ions through the receptor channel, leading to an overall increase in GABAergic neuronal transmission. This increased transmission produces widespread CNS effects such as sedation, antiepileptic and anxiolytic effects, and hypnotic behaviors.

S-8510. Shionogi and GlaxoSmithKline are codeveloping S-8510/SB 737552, a BZD inverse agonist, for Alzheimer’s disease and mild to moderate senile dementia. The drug is in Phase I trials in Europe and Phase II trials in Japan for Alzheimer’s disease and dementia. S-8510 is a BZD partial inverse agonist to the BZD site on the GABA-A receptors in the central nervous system. As an inverse agonist (which as a group elicit CNS effects such as insomnia, agitation, and proconvulsant behaviors), S-8510 functions as a negative modulator of the GABA-A receptor. S-8510, however, is a partial inverse agonist, which means it has a lower affinity for the BZD binding site than do full agonists, and studies in animals have shown that the drug does not induce convulsions or anxiety. In additional animal studies, S-8510 has increased the extracellular levels of acetylcholine and norepinephrine (NE) in the hippocampus and frontal cortex regions of the brain, two areas where Alzheimer’s disease patients experience a significant loss of cholinergic and monoaminergic neurons that results in cognitive and behavioral changes.

Phase I and II clinical trial data are not available. In animal studies, however, S-8510 reduced pharmacologically induced memory and learning impairments (). The side-effect profile of the drug appears to be favorable in animals, with no convulsions or anxiety induced at doses beyond the cognitively effective doses ().

With its activity aimed at the CNS GABA receptor, S-8510 is not a disease-modifying therapy, but it offers a unique mechanism of action for increasing acetylcholine activity in the brain and the potential to ameliorate Alzheimer’s disease symptoms. The negative side effects associated with inverse agonists of GABA receptors (including convulsions, agitation, and wakefulness) are somewhat mitigated by the partial activity of this drug at the receptor site; this partial activity suggests a promising side-effect profile for S-8510.

Should S-8510 prove successful at attenuating the loss of acetylcholine in Alzheimer’s disease patients, it still appears to have considerable barriers to overcome before it can be commercially successful. The most significant hurdle for this drug is the potential induction of wakefulness in a population that commonly experiences insomnia and agitation during the progression of Alzheimer’s disease. Preclinical studies demonstrate that S-8510 increases the wakefulness stage of sleep-wakefulness cycles in aged monkeys, but not in young monkeys, in a dose-dependent-manner. These data suggest that S-8510 may provoke insomnia in elderly patients, a side effect that would not have been detected in Phase I trials in healthy young volunteers. Many Alzheimer’s disease patients suffer from sleep disturbances, agitation, and aggression; a drug that induces wakefulness would likely meet with skepticism from patients and care-givers alike, unless combination therapy with other drugs can diminish these effects. Finally, to penetrate a marketplace of well-established AChEI drugs, S-8510 must prove to be more effective at delaying disease progression than the currently established drugs, and this ability has yet to be demonstrated in clinical trials.