ABT-089, also known as Pozanicline, is an experimental compound developed by Abbott. It was investigated for its nootropic (cognitive-enhancing) and neuroprotective properties, aiming to address various neurological and neurodevelopmental conditions.
How ABT-089 Interacts with the Brain
ABT-089 functions as a neuronal nicotinic acetylcholine receptor (nAChR) agonist, activating these specific receptors in the brain. It primarily shows selectivity for the alpha4beta2 (α4β2) nAChR subtype, acting as a partial agonist. The compound also exhibits partial agonism at the alpha6beta2 (α6β2) subtype, but not at the alpha7 (α7) or alpha3beta4 (α3β4) subtypes. Modulating these receptors influences the release of neurotransmitters like acetylcholine and dopamine, which play roles in brain functions such as attention, memory, and learning. Animal research indicates ABT-089 can enhance cognitive function and offer neuroprotection against excitotoxic glutamate insults. Its activity at alpha6beta2 nAChRs, which are sensitive to sub-micromolar concentrations, may contribute to its cognitive-enhancing effects at low doses.
Investigated Uses of ABT-089
ABT-089 has been investigated for its therapeutic potential in several neurological and neurodevelopmental disorders involving cognitive deficits. A primary focus was Attention-Deficit/Hyperactivity Disorder (ADHD), where it was explored to improve attention and reduce hyperactivity. Animal studies suggested its usefulness for ADHD, leading to human trials. It was also investigated for neurodegenerative diseases like Alzheimer’s, given its role in modulating neurotransmission related to memory and learning. Additionally, researchers considered its use in schizophrenia and schizoaffective disorders, conditions that can involve cognitive impairments. The rationale for these investigations stemmed from ABT-089’s ability to enhance cognitive functioning in animal models.
Current Research and Trial Status
ABT-089 has undergone clinical trials to assess its efficacy and safety in humans. In adults with ADHD, a proof-of-concept study indicated significant improvement in ADHD symptoms compared to placebo. A subsequent larger crossover study in adults also reported that ABT-089, at a dose of 40 mg given once or twice daily, was superior to placebo in ADHD outcomes and generally well tolerated. However, results in pediatric populations were different. Two multicenter, randomized, double-blind, placebo-controlled studies involving children aged 6 to 12 years with ADHD did not show the same level of efficacy. In these pediatric trials, ABT-089 did not demonstrate statistically significant improvement on the primary efficacy variable, the ADHD-RS-IV (HV) Total Score, or other measures of ADHD symptomatology.
Safety Considerations and Side Effects
The safety profile of ABT-089 has been evaluated in clinical trials. In adult studies, ABT-089 was generally well tolerated at doses up to 80 mg. Common adverse events included nasopharyngitis (6.6%), upper respiratory tract infection (6.6%), and somnolence (5.7%). The incidence of adverse events did not significantly differ between active treatment groups and placebo. Preclinical studies indicated that ABT-089 had minimal effects on dopaminergic transmission, suggesting it might not be associated with concerns like abuse liability or insomnia, often seen with nicotine. It also showed little propensity to induce adverse effects such as ataxia, hypothermia, seizures, or significant cardiovascular or gastrointestinal side effects. In pediatric trials, ABT-089’s safety profile was similar to placebo.