In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer's disease.
We previously reported that alpha7 nicotinic acetylcholine receptor (nAChR) agonism produces efficacy in preclinical cognition models correlating with activation of cognitive and neuroprotective signaling pathways associated with Alzheimer's disease (AD) pathology. In the present studies, the selective and potent alpha7 nAChR agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole (ABT-107) was evaluated in behavioral assays representing distinct cognitive domains. Studies were also conducted to address potential issues that may be associated with the clinical development of an alpha7 nAChR agonist. Specifically, ABT-107 improved cognition in monkey delayed matching to sample, rat social recognition, and mouse two-trial inhibitory avoidance, and continued to improve cognitive performance at injection times when exposure levels continued to decline. Rats concurrently infused with ABT-107 and donepezil at steady-state levels consistent with clinical exposure showed improved short-term recognition memory. Compared with nicotine, ABT-107 did not produce behavioral sensitization in rats or exhibit psychomotor stimulant activity in mice. Repeated (3 days) daily dosing of ABT-107 increased extracellular cortical acetylcholine in rats, whereas acute administration increased cortical extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation in mice, neurochemical and biochemical events germane to cognitive function. ABT-107 increased cortical phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3, a primary tau kinase associated with AD pathology. In addition, continuous infusion of ABT-107 in tau/amyloid precursor protein transgenic AD mice reduced spinal tau hyperphosphorylation. These findings show that targeting alpha7 nAChRs may have potential utility for symptomatic alleviation and slowing of disease progression in the treatment AD, and expand the understanding of the potential therapeutic viability associated with the alpha7 nAChR approach in the treatment of AD.
Bitner
R Scott
RS
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. robert.s.bitner@abbott.com
Bunnelle
William H
WH
Decker
Michael W
MW
Drescher
Karla U
KU
Kohlhaas
Kathy L
KL
Markosyan
Stella
S
Marsh
Kennan C
KC
Nikkel
Arthur L
AL
Browman
Kaitlin
K
Radek
Rich
R
Anderson
David J
DJ
Buccafusco
Jerry
J
Gopalakrishnan
Murali
M
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000633:toxicity; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D000077265:Donepezil; D004569:Electroencephalography / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D007189:Indans / Q000494:pharmacology; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018722:Nicotinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011812:Quinuclidines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects; D012938:Social Perception; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins / Q000235:genetics / Q000633:toxicity
C552256:5-(6-(1-azabicyclo(2,2,2)oct-3-yloxy)pyridazin-3-yl)-1H-indole; D016564:Amyloid beta-Protein Precursor; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D007189:Indans; D007211:Indoles; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D010880:Piperidines; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins; D000077265:Donepezil; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D000109:Acetylcholine