title: Concentration-response relationship of the α7 nicotinic acetylcholine receptor agonist FRM-17874 across multiple in vitro and in vivo assays.
abstract: Pharmacological activation of α7 nicotinic acetylcholine receptors (α7 nAChRs) may improve cognition in schizophrenia and Alzheimer's disease. The present studies describe an integrated pharmacological analysis of the effects of FRM-17874, an analogue of encenicline, on α7 nAChRs in vitro and in behavioral and neurophysiological assays relevant to cognitive function. FRM-17874 demonstrated high affinity binding to human α7 nAChRs, displacing [(3)H]-methyllacaconitine (Ki=4.3nM). In Xenopus laevis oocytes expressing human α7 nAChRs, FRM-17874 acted as an agonist, evoking inward currents with an EC50 of 0.42μM. Lower concentrations of FRM-17874 (0.01-3nM) elicited no detectable current, but primed receptors to respond to sub-maximal concentrations of acetylcholine. FRM-17874 improved novel object recognition in rats, and enhanced memory acquisition and reversal learning in the mouse water T-maze. Neurophysiological correlates of cognitive effects of drug treatment, such as synaptic transmission, long-term potentiation, and hippocampal theta oscillation were also evaluated. Modulation of synaptic transmission and plasticity was observed in rat hippocampal slices at concentrations of 3.2 and 5nM. FRM-17874 showed a dose-dependent facilitation of stimulation-induced hippocampal theta oscillation in mice and rats. The FRM-17874 unbound brain concentration-response relationship for increased theta oscillation power was similar in both species, exhibited a biphasic pattern peaking around 3nM, and overlapped with active doses and exposures observed in cognition assays. In summary, behavioral and neurophysiological assays indicate a bell-shaped effective concentration range and this report represents the first attempt to explain the concentration-response function of α7 nAChR-mediated pro-cognitive effects in terms of receptor pharmacology.
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, 310 Cedar St., New Haven, CT 06520, USA. Electronic address: milan.stoiljkovic@yale.edu.
authors.forename: Milan
authors.initials: M
authors.lastname: Stoiljkovic
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: lleventhal@forumpharma.com.
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: achen@forumpharma.com.
authors.forename: Angela
authors.initials: A
authors.lastname: Chen
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: tchen@forumpharma.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: rdriscoll@forumpharma.com.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Driscoll
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: dflood@forumpharma.com.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Flood
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: hhodgdon@forumpharma.com.
authors.forename: Hilliary
authors.initials: H
authors.lastname: Hodgdon
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: rhurst@forumpharma.com.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hurst
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, 310 Cedar St., New Haven, CT 06520, USA. Electronic address: david.nagy@yale.edu.
authors.forename: David
authors.initials: D
authors.lastname: Nagy
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: tpiser@forumpharma.com.
authors.forename: Timothy
authors.initials: T
authors.lastname: Piser
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: ctang@forumpharma.com.
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: mtownsend@forumpharma.com.
authors.forename: Matthew
authors.initials: M
authors.lastname: Townsend
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: ztu@forumpharma.com.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Tu
authors.affiliation: HiQScreen Sàrl, 6, rte de Compois, 1222 Vésenaz, Geneva, Switzerland. Electronic address: daniel.bertrand@hiqscreen.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: FORUM Pharmaceuticals Inc., 225 Second Avenue, Waltham, MA 02451, USA. Electronic address: gkoenig@forumpharma.com.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Koenig
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, 310 Cedar St., New Haven, CT 06520, USA. Electronic address: mihaly.hajos@yale.edu.
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajós
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*
chemical_list: C000604696:7-fluoro-N-quinuclidin-3-yl)benzo(b)thiophene-2-carboxamide; D011812:Quinuclidines; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Alzheimer’s disease; Cognition; Concentration-response relationship; Schizophrenia; Theta oscillation; α7 nAChR agonist