title: 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.
authors.affiliation: 1 Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, USA.
authors.forename: Kelvin W
authors.initials: KW
authors.lastname: Gee
authors.affiliation: 2 Department of Psychiatry, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.affiliation: 3 Anvyl LLC, 18092 Sky Park South, Suite F, Irvine, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kanner
authors.affiliation: 2 Department of Psychiatry, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Johnson
authors.affiliation: 1 Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, USA.
authors.forename: Derk
authors.initials: D
authors.lastname: Hogenkamp
authors.affiliation: 2 Department of Psychiatry, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Josette
authors.initials: J
authors.lastname: Harris
authors.affiliation: 1 Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, USA.
authors.forename: Minhtam
authors.initials: M
authors.lastname: Tran
authors.affiliation: 2 Department of Psychiatry, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Edmonds
authors.affiliation: 4 Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, USA.
authors.forename: William
authors.initials: W
authors.lastname: Sauer
authors.affiliation: 1 Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Yoshimura
authors.affiliation: 1 Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Johnstone
authors.affiliation: 2 Department of Psychiatry, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
mesh_terms: D000328:Adult; D000494:Allosteric Regulation / Q000187:drug effects*; D000813:Anilides / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D019965:Neurocognitive Disorders / Q000188:drug therapy* / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D055815:Young Adult; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C000621157:AVL3288; D000813:Anilides; D015415:Biomarkers; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine
keywords: Receptors; allosteric modulators; cognition; drug evaluation; nicotinic; schizophrenia