In Vitro Pharmacological Characterization of a Novel Selective 7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

Enhancement of 7 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 7 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 7 nAChRs [rat or human cortex, [H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539), Ki 0.2–0.6 nM or [H]methyllycaconitine (MLA), 7 nM] that was at least 100-fold selective versus non7 nAChRs and other receptors. Functionally, ABT-107 did not evoke detectible currents in Xenopus oocytes expressing human or nonhuman 3 4, chimeric ( 6/ 3) 4, or 5-HT3A receptors, and weak or negligible Ca responses in human neuroblastoma IMR-32 cells ( 3* function) and human 4 2 and 4 4 nAChRs expressed in human embryonic kidney 293 cells. ABT-107 potently evoked human and rat 7 nAChR current responses in oocytes (EC50, 50–90 nM total charge, 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 7-like currents, which were inhibited by the 7 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 7 PAM [A-867744 or N-[(3R)-1azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU120596)], the addition of ABT-107 elicited MLA-sensitive 7 nAChRmediated Ca 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 7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.