TY - JOUR T1 - Distinct Profiles of α7 nAChR Positive Allosteric Modulation Revealed by Structurally Diverse Chemotypes JF - Molecular Pharmacology JO - Mol Pharmacol SP - 715 LP - 724 DO - 10.1124/mol.107.035410 VL - 72 IS - 3 AU - Jens Halvard Grønlien AU - Monika Håkerud AU - Hilde Ween AU - Kirsten Thorin-Hagene AU - Clark A. Briggs AU - Murali Gopalakrishnan AU - John Malysz Y1 - 2007/09/01 UR - http://molpharm.aspetjournals.org/content/72/3/715.abstract N2 - Selective modulation of α7 nicotinic acetylcholine receptors (nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target α7 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 α7 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 α7 nAChRs were desensitized, type II, but not type I, PAMs could reactivate α7 currents. Both types of PAMs also increased the ACh-evoked α7 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 α4β2 or α3β4 nAChRs, although some inhibition was noted for 5-HI, genistein, and TQS. In summary, our studies reveal two distinct α7 PAM profiles, which could offer unique opportunities for modulating α7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications. The American Society for Pharmacology and Experimental Therapeutics ER -