title: The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance.
abstract: (5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane) (BuTAC) is a novel, selective muscarinic receptor ligand with partial agonist mode of action at muscarinic M2 and M4 and antagonist mode of action at M1, M3 and M5 receptor subtypes in cloned cell lines. BuTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for dopamine receptors, and parasympathomimetic effects in mice are produced only at doses well beyond the doses exhibiting the antipsychotic-like effects. In the present study we investigated the effects of BuTAC and the antipsychotic compounds clozapine, sertindole and olanzapine using one trial passive avoidance with mice as a model of learning and memory. Pharmacologically relevant doses of BuTAC and reference antipsychotics were identified, based on inhibition of apomorphine-induced climbing in mice as an assay measuring antidopaminergic potency. When ratios between the minimum effective dose (MED) for impairment of retention in passive avoidance and the MED for inhibition of apomorphine-induced climbing were calculated, BuTAC displayed a high ratio of >10, compared with clozapine (0.3), sertindole (3) and olanzapine (3). These data suggest that BuTAC is a potential novel antipsychotic which may have favourable effects on aspects of learning and memory.
authors.affiliation: Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Rasmussen
authors.forename: A
authors.initials: A
authors.lastname: Fink-Jensen
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: L
authors.initials: L
authors.lastname: Jeppesen
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: N W
authors.initials: NW
authors.lastname: DeLapp
authors.forename: C
authors.initials: C
authors.lastname: Whitesitt
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents; D011976:Receptors, Muscarinic