title: AF710B, a Novel M1/σ1 Agonist with  Therapeutic Efficacy in Animal Models of  Alzheimer’s Disease.
abstract: We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 µg/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve σ1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 nM), via activation of M1 and a possible involvement of σ1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 µM) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 µg/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3β activity, p25/CDK5, neuroinflammation, soluble and insoluble Aβ40, Aβ42, plaques and tau pathologies. AF710B differs from conventional σ1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies.
authors.forename: Abraham
authors.initials: A
authors.lastname: Fisher
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
authors.forename: Lili
authors.initials: L
authors.lastname: Wu
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Ryskamp
authors.forename: Nira
authors.initials: N
authors.lastname: Bar-Ner
authors.forename: Niva
authors.initials: N
authors.lastname: Natan
authors.forename: Rachel
authors.initials: R
authors.lastname: Brandeis
authors.forename: Hanoch
authors.initials: H
authors.lastname: Elkon
authors.forename: Victoria
authors.initials: V
authors.lastname: Nahum
authors.forename: Eitan
authors.initials: E
authors.lastname: Gershonov
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000610755:AF710 compound; D018697:Nootropic Agents; D043643:Receptor, Muscarinic M1; D017480:Receptors, sigma; D013141:Spiro Compounds; D053778:Thiazolidines