A-582941

A-582941 is a selective α7nAChR agonist that is orally active and capable of crossing the blood-brain barrier. It exhibits Ki values of 10.8 nM in rat brains and 17 nM in the human frontal cortex. The compound also acts as an agonist at 5-HT3 receptors with a Ki of 150 nM. A-582941 is known to induce phosphorylation of ERK1/2 and CREB, inhibit GSK-3β via Ser-9 phosphorylation, increase acetylcholine release, and stimulate the expression of Arc and c-Fos. This activation occurs in brain regions associated with working memory and attention, and A-582941 reduces cell death caused by nerve growth factor (NGF) deprivation. It is applicable in research on Alzheimer's disease and schizophrenia.

5-HT3 Receptor:150 nM (Ki)

A-582941 binds with high affinity to α7 nicotinic acetylcholine receptors (nAChRs) in rat brains (K i = 10.8 nM) and human frontal cortex membranes (K i = 17 nM), while showing slightly lower affinity for antagonist-labeled α7 nAChRs in rat brains (K i = 88 nM). It acts as a partial agonist of recombinant human α7 nAChR in Xenopus oocytes, with an EC 50 of 4260 nM and 52% efficacy relative to acetylcholine. For recombinant rat α7 nAChRs in Xenopus oocytes, A-582941 has an EC 50 of 2450 nM and 60% efficacy compared to acetylcholine. After pre-incubation with 3 μM PNU-120596, A-582941 shows enhanced potency (EC 50 = 580 nM) and efficacy (207% relative to acetylcholine) on recombinant human α7 nAChR in Xenopus oocytes. In PC12 cells expressing α7 nAChR, A-582941 enhances ERK1/2 phosphorylation with an EC 50 of 95 nM, mediated by α7 nAChRs. Additionally, A-582941 (0.1-100 μM) protects PC12 cells from cell death induced by NGF withdrawal and does not induce proliferation in cultured human keratinocytes (100 nM-10,000 nM; 9 days).

A-582941, administered intraperitoneally at doses ranging from 0.01 to 1.00 μmol/kg, enhances dose-dependent phosphorylation of ERK1/2 and CREB in cognitive-related regions of the mouse brain and improves memory consolidation in mice, achieving full efficacy at 0.1 μmol/kg. At doses of 0.1 to 1.0 μmol/kg given intraperitoneally, it increases Ser-9 GSK-3β phosphorylation in the mouse cingulate cortex and improves short-term recognition memory in rats, reaching full efficacy at 0.1 μmol/kg. A single daily intraperitoneal dose of 3 μmol/kg over 3 days moderately raises acetylcholine release in the medial prefrontal cortex of rats. Subcutaneous continuous infusion at 1.8 μmol/kg for 7 days maintains its efficacy in enhancing rat short-term recognition memory. When administered intramuscularly at 0.003 to 0.100 μmol/kg, A-582941 improves working memory in young rhesus monkeys, achieving full efficacy at 0.01 μmol/kg. A dose of 10 μmol/kg intraperitoneally reverses sensory gating deficiencies induced by MLA in rats. Genetic sensory gating deficits in DBA/2J mice are mitigated by 3 to 10 μmol/kg intraperitoneally, with 5 days of administration at 3 μmol/kg maintaining efficacy. Subcutaneous doses of 0.1 to 1.0 μmol/kg slightly enhance response inhibition/impulsive behavior in spontaneously hypertensive juvenile rats. In juvenile male Wistar rats, subcutaneous administration of 0.1 to 10 mg/kg induces a dose-dependent increase in Arc and c-Fos mRNA and protein expression in the forebrain, with a 10 mg/kg dose achieving maximal effects and greater reactivity compared to adult rats. However, in adult male Wistar rats, a 10 mg/kg subcutaneous dose increases Arc and c-Fos immunoreactive cells without inducing detectable mRNA elevation in any assessed regions. Lastly, an intramuscular dose of 1.14 to 38 μg/kg significantly enhances the accuracy of delayed match-to-sample tasks in young rhesus monkeys, with a 22.2% improvement in long-delay trials, double that of short-delay trials; however, this enhancement dissipates 24 hours post-administration.