First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288

Abstract

Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.

Nicotine modulates human brain plasticity via calcium‐dependent mechanisms

“…; Gee et al . ). The present study suggests that substance administration and dose determination need to be carefully addressed because too high or too low calcium concentrations might compromise functions.…”

Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia

“…However, our findings could be specific to the brief duration, procedures used, and single dose tested. Longer duration and a broader dose range of this or perhaps other α7 nAChR PAMs may show efficacy for smoking cessation (eg, Marcus et al, 2016;Gee et al, 2017).…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…These subtypes are formed by various combinations of five homologous subunits (α1–10, β1–4, γ, δ, and ϵ) organized around a central pore known as an ion channel . One of the most prominent nAChR subtypes expressed in the brain and neurons is α7, located in regions associated with memory and learning; it is involved in diseases such as AD and schizophrenia …”

“…[43] One of the most prominentn AChRs ubtypes expressed in the brain and neurons is a7, located in regions associated with memory and learning; it is involved in diseases such as AD and schizophrenia. [39,44] a7n AChRi sp resent on synaptic regionsa nd is therefore directly relatedt on eurotransmission. For instance, ACh, as its natural agonist, activates this receptor fors ignaling in the synapse.…”

“…[53] The fact that AVL-3288a cts at more than one target with different purposes could meanith as poor selectivity; [68] however,m ore recent indicationss uggest that this compound may be safely administered to humans, and so its development is still on ap ositive path as ad rug candidate for treating CNS disorders. [44] Some other PAMs of a7n AChR are genistein (3,F igure 1), which is related to the enhancement of associativel earning and neuroprotection. [51,69] Also, compounds NS-1738 (6)a nd PNU120596 (5)( Figure 1) improves patiall earninga sw ell as workinga nd recognition memory.…”