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Distinct Profiles of 7 nAChR Positive Allosteric Modulation Revealed by Structurally Diverse Chemotypes

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois (C.A.B., M.G., J.M.) and Oslo Research Park, Oslo, Norway (J.H.G., M.H., H.W., K.T.H.)

Selective modulation of 7 nicotinic acetylcholine receptors (nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target 7 nAChRs is by positive allosteric modulation. Structurally diverse compounds, including PNU-120596, 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), and 5-hydroxyindole (5-HI) have been identified as positive allosteric modulators (PAMs), but their receptor interactions and pharmacological profiles remain to be fully elucidated. In this study, we investigated interactions of these compounds at human 7 nAChRs, expressed in Xenopus laevis oocytes, along with genistein, a tyrosine kinase inhibitor. Genistein was found to function as a PAM. Two types of PAM profiles were observed. 5-HI and genistein predominantly affected the apparent peak current (type I) whereas PNU-120596 and TQS increased the apparent peak current and evoked a distinct weakly decaying current (type II). Concentration-responses to agonists [ACh, 3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine dihydrochloride (GTS-21), and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987)] were potentiated by both types, although type II PAMs had greater effects. When applied after 7 nAChRs were desensitized, type II, but not type I, PAMs could reactivate 7 currents. Both types of PAMs also increased the ACh-evoked 7 window currents, with type II PAMs generally showing larger potentiation. None of the PAMs tested increased nicotine-evoked Ca²⁺ transients in human embryonic kidney 293 cells expressing human 42 or 34 nAChRs, although some inhibition was noted for 5-HI, genistein, and TQS. In summary, our studies reveal two distinct 7 PAM profiles, which could offer unique opportunities for modulating 7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.

Address correspondence to: Dr. John Malysz, Neuroscience Research Abbott, Global Pharmaceutical Research and Development, Dept R47W, Bldg AP9A, 100 Abbott Park Road, Abbott Park, IL 60064-6125. E-mail: john.malysz{at}abbott.com

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