In vitro pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107.
Enhancement of alpha7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective alpha7 nAChR agonist, 5-(6-[(3R)-1-azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107). ABT-107 displayed high affinity binding to alpha7 nAChRs [rat or human cortex, [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539), K(i) = 0.2-0.6 nM or [(3)H]methyllycaconitine (MLA), 7 nM] that was at least 100-fold selective versus non-alpha7 nAChRs and other receptors. Functionally, ABT-107 did not evoke detectible currents in Xenopus oocytes expressing human or nonhuman alpha3beta4, chimeric (alpha6/alpha3)beta4, or 5-HT(3A) receptors, and weak or negligible Ca(2+) responses in human neuroblastoma IMR-32 cells (alpha3* function) and human alpha4beta2 and alpha4beta4 nAChRs expressed in human embryonic kidney 293 cells. ABT-107 potently evoked human and rat alpha7 nAChR current responses in oocytes (EC(50), 50-90 nM total charge, approximately 80% normalized to acetylcholine) that were enhanced by the positive allosteric modulator (PAM) 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (A-867744). In rat hippocampus, ABT-107 alone evoked alpha7-like currents, which were inhibited by the alpha7 antagonist MLA. In dentate gyrus granule cells, ABT-107 enhanced spontaneous inhibitory postsynaptic current activity when coapplied with A-867744. In the presence of an alpha7 PAM [A-867744 or N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-120596)], the addition of ABT-107 elicited MLA-sensitive alpha7 nAChR-mediated Ca(2+) signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity alpha7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.
Malysz
John
J
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064-6125, USA. john.malysz@abbott.com
Anderson
David J
DJ
Grønlien
Jens H
JH
Ji
Jianguo
J
Bunnelle
William H
WH
Håkerud
Monika
M
Thorin-Hagene
Kirten
K
Ween
Hilde
H
Helfrich
Rosalind
R
Hu
Min
M
Gubbins
Earl
E
Gopalakrishnan
Sujatha
S
Puttfarcken
Pamela S
PS
Briggs
Clark A
CA
Li
Jinhe
J
Meyer
Michael D
MD
Dyhring
Tino
T
Ahring
Philip K
PK
Nielsen
Elsebet Ø
EØ
Peters
Dan
D
Timmermann
Daniel B
DB
Gopalakrishnan
Murali
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000096926:Benzenesulfonamides
D002118:Calcium; D018691:Excitatory Amino Acid Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases; D007211:Indoles; D007555:Isoxazoles; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D011758:Pyrroles; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C542089:4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C552256:5-(6-(1-azabicyclo(2,2,2)oct-3-yloxy)pyridazin-3-yl)-1H-indole; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat