title: Chalcones as positive allosteric modulators of α7 nicotinic acetylcholine receptors: a new target for a privileged structure.
abstract: The α7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain and inflammation among other diseases. Therefore, the development of new agents that target this receptor has great significance. Positive allosteric modulators might be advantageous, since they facilitate receptor responses without directly interacting with the agonist binding site. Here we report the search for and further design of new positive allosteric modulators having the relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chalcones substituted with hydroxyl groups at defined locations were identified as optimal and specific promoters of α7 nicotinic function. The most potent compound (2,4,2',5'-tetrahydroxychalcone, 111) was further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer, opening the way for future developments around the chalcone structure.
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Balsera
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, Ramon y Cajal s/n, 03050 Sant Joan d'Alacant, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Mulet
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernandez, Av. de la Universidad s/n, 03202 Elche, Spain.
authors.forename: Asia
authors.initials: A
authors.lastname: Fernández-Carvajal
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernandez, Av. de la Universidad s/n, 03202 Elche, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: de la Torre-Martínez
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernandez, Av. de la Universidad s/n, 03202 Elche, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.affiliation: Departamento de Farmacología, Universidad de La Laguna, La Cuesta s/n, 38200 La Laguna, Tenerife, Spain.
authors.forename: José G
authors.initials: JG
authors.lastname: Hernández-Jiménez
authors.affiliation: Departamento de Farmacología, Universidad de La Laguna, La Cuesta s/n, 38200 La Laguna, Tenerife, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Estévez-Herrera
authors.affiliation: Departamento de Farmacología, Universidad de La Laguna, La Cuesta s/n, 38200 La Laguna, Tenerife, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Borges
authors.affiliation: Instituto Teófilo Hernando, Departamento de Farmacología, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Andiara E
authors.initials: AE
authors.lastname: Freitas
authors.affiliation: Instituto Teófilo Hernando, Departamento de Farmacología, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: García-López
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: González-Muñiz
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Pérez de Vega
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, Ramon y Cajal s/n, 03050 Sant Joan d'Alacant, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Valor
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, Ramon y Cajal s/n, 03050 Sant Joan d'Alacant, Spain.
authors.forename: Lucie
authors.initials: L
authors.lastname: Svobodová
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, Ramon y Cajal s/n, 03050 Sant Joan d'Alacant, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Sala
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, Ramon y Cajal s/n, 03050 Sant Joan d'Alacant, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sala
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, Ramon y Cajal s/n, 03050 Sant Joan d'Alacant, Spain. Electronic address: manuel.criado@umh.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Criado
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009840:Oligomycins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D047188:Chalcones; D009840:Oligomycins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D012402:Rotenone; C031004:oligomycin A
keywords: Analgesia; Chalcones; Neuroprotection; Positive allosteric modulators; α7 Nicotinic receptor