A-582941

A-582941 is a selective, orally active, blood-brain barrier-permeable α7 nAChR agonist, with K_i values of 10.8 nM and 17 nM in rat brain and human frontal cortex, respectively. A-582941 exhibits agonistic activity at 5-HT3 receptors, with a K_i of 150 nM. A-582941 triggers phosphorylation of ERK1/2 and CREB, inhibits GSK-3β via Ser-9 phosphorylation, increases acetylcholine release, induces the expression of Arc and c-Fos, activates brain regions associated with working memory and attention, and reduces cell death caused by nerve growth factor (NGF) deprivation. A-582941 is applicable for the research of Alzheimer's disease and schizophrenia^[1][2][3]. In Vitro:A-582941 binds with high affinity to α7 nAChRs in rat brain (K_i = 10.8 nM) and human frontal cortex (K_i = 17 nM) membranes, with slightly lower affinity for antagonist-labeled α7 nAChRs (K_i = 88 nM) in rat brain^[1].
A-582941 acts as a partial agonist at recombinant human α7 nAChRs in Xenopus oocytes, with an EC₅₀ of 4260 nM and 52% efficacy relative to acetylcholine^[1].
A-582941 acts as a partial agonist at recombinant rat α7 nAChRs in Xenopus oocytes, with an EC₅₀ of 2450 nM and 60% efficacy relative to acetylcholine^[1].
A-582941 (3 μM PNU-120596 pre-incubated prior to treatment) exhibits increased potency (EC₅₀ = 580 nM) and efficacy (207% relative to acetylcholine) at recombinant human α7 nAChRs in Xenopus oocytes^[1].
A-582941 increases ERK1/2 phosphorylation in α7 nAChR-expressing PC12 cells with an EC₅₀ of 95 nM, an effect mediated by α7 nAChRs^[1].
A-582941 (0.1-100 μM) protects PC12 cells from NGF withdrawal-induced cell death^[1].
A-582941 (100 nM-10,000 nM; 9 days) does not induce proliferation in cultured human keratinocytes^[1]. In Vivo:A-582941 (0.01-1.00 μmol/kg; i.p.) dose-dependently increases ERK1/2 and CREB phosphorylation in mouse brain regions involved in cognition^[1].
A-582941 (0.01-1.00 μmol/kg; i.p.) improves memory consolidation in mice, with full efficacy achieved at 0.1 μmol/kg (i.p.)^[1].
A-582941 (0.1-1.0 μmol/kg; i.p.) dose-dependently increases Ser-9 GSK-3β phosphorylation in the mouse cingulate cortex^[1].
A-582941 (0.1-1.0 μmol/kg; i.p.) improves short-term recognition memory in rats, with full efficacy achieved at 0.1 μmol/kg (i.p.)^[1].
A-582941 (3 μmol/kg; i.p.; once daily; 3 consecutive days) moderately increases medial prefrontal cortex acetylcholine release in freely moving rats^[1].
A-582941 (1.8 μmol/kg/day; s.c.; continuous infusion; 7 days) maintains efficacy in improving rat short-term recognition memory^[1].
A-582941 (0.003-0.100 μmol/kg; i.m.) improves working memory in young Rhesus monkeys, with full efficacy achieved at 0.01 μmol/kg (i.m.)^[1].
A-582941 (10 μmol/kg; i.p.) reverses MLA (HY-N2332)-induced sensory gating deficit in rats^[1].
A-582941 (3-10 μmol/kg; i.p.) improves genetic sensory gating deficit in DBA/2J mice, with efficacy retained after 5 consecutive days of 3 μmol/kg (i.p.) dosing^[1].
A-582941 (0.1-1.0 μmol/kg; s.c.) modestly improves response inhibition/impulsivity in spontaneously hypertensive rat pups^[1].
A-582941 (0.1-10 mg/kg; s.c.; single dose) induces dose-dependent increases in Arc and c-Fos mRNA and protein expression in limbic forebrain regions of juvenile male Wistar rats, with maximal effects at 10 mg/kg and greater responsiveness observed in juvenile compared to adult rats^[2].
A-582941 (0.1-10 mg/kg; s.c.; single dose) increases Arc and c-Fos immunoreactive cell counts in limbic forebrain regions of adult male Wistar rats at 10 mg/kg, but does not induce measurable increases in Arc or c-Fos mRNA expression in any examined region^[2].
A-582941 (1.14-38 μg/kg; i.m.; single dose) significantly improves delayed matching-to-sample task accuracy in young adult Rhesus monkeys, with a 22.2% increase in long delay trial accuracy (twice the magnitude of improvement in short delay trials) that is not sustained 24 hours after dosing^[3].