title: Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
abstract: Selective modulation of alpha7 nicotinic acetylcholine receptors (nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target alpha7 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 alpha7 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 alpha7 nAChRs were desensitized, type II, but not type I, PAMs could reactivate alpha7 currents. Both types of PAMs also increased the ACh-evoked alpha7 window currents, with type II PAMs generally showing larger potentiation. None of the PAMs tested increased nicotine-evoked Ca(2+) transients in human embryonic kidney 293 cells expressing human alpha4beta2 or alpha3beta4 nAChRs, although some inhibition was noted for 5-HI, genistein, and TQS. In summary, our studies reveal two distinct alpha7 PAM profiles, which could offer unique opportunities for modulating alpha7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.
authors.affiliation: Oslo Research Park, Oslo, Norway.
authors.forename: Jens Halvard
authors.initials: JH
authors.lastname: Grønlien
authors.forename: Monika
authors.initials: M
authors.lastname: Håkerud
authors.forename: Hilde
authors.initials: H
authors.lastname: Ween
authors.forename: Kirsten
authors.initials: K
authors.lastname: Thorin-Hagene
authors.forename: Clark A
authors.initials: CA
authors.lastname: Briggs
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: John
authors.initials: J
authors.lastname: Malysz
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D008845:Microinjections; D009281:Naphthalenes / Q000737:chemistry; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry; D011950:Receptors, Cholinergic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000737:chemistry; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C523471:4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta(c)quinoline-8-sulfonic acid amide; D001549:Benzamides; D001597:Benzylidene Compounds; D001643:Bridged Bicyclo Compounds; C579167:Chrna7 protein, human; D004791:Enzyme Inhibitors; D007211:Indoles; D007555:Isoxazoles; D009281:Naphthalenes; D018733:Nicotinic Antagonists; C498513:PNU-282987; D010671:Phenylurea Compounds; D011725:Pyridines; D011804:Quinolines; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; C026785:5-hydroxyindole; D009538:Nicotine; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D000109:Acetylcholine; D002118:Calcium