A-582941 (dihydrochloride)

A-582941 dihydrochloride is a potent, selective and brain-penetrant partial agonist of α7 nAChR, with K_is of 10.8 and 16.7 nM in rat brain membranes and human frontal cortex, respectively. A-582941 dihydrochloride also binds to human 5-HT₃ receptor with a K_i of 150 nM. A-582941 has the potential for cognitive deficits associated with various neurodegenerative and psychiatric disorders research^[1][2]. In Vitro:A-582941 (0.1-100 μM) protects against cell death induced by NGF withdrawal in PC12 cells^[2].
A-582941 (100 nM) increases the number of inhibitory postsynaptic potentials (IPSCs) by 260±70%, the sum of amplitudes by 220±30%, and the sum of areas by 210±40%^[2].
A-582941 increases ERK1/2 phosphorylation with an EC₅₀ of 95 nM in PC12 cells^[2]. In Vivo:A-582941 (3 μM/kg, i.p. once daily for 3 d) induces a moderate increase in ACh release in the medial prefrontal cortex (mPFCx) of freely moving rats^[2].
A-582941 (0.01-1.00 μM/kg, i.p.) produces a dose-dependent increase in ERK1/2 phosphorylation in the cingulate cortex and hippocampus, and increases cAMP response element-binding protein (CREB) phosphorylation in the cingulate cortex in mice^[2].
A-582941 (0.1-1.0 μM/kg, i.p.) evokes dose-dependent increases in Ser-9 GSK-3β phosphorylation in the mouse cingulate cortex^[2].
A-582941 shows high oral bioavailability (mouse ~100%, rat 90%, dog 22%, monkey 50%) and C_max (mouse 18, rat 114, dog 79, monkey 39 ng/mL) following oral administration (mouse 1.0, rat 6.2, dog 3.0, monkey 3.0 μM/kg)^[2].
A-582941 shows terminal elimination half-lives (mouse 1.4, rat 1.5, dog 1.4, monkey 2.0 h), plasma clearance (mouse 7.9, rat 4.7, dog 5.3, monkey 1.6 L/h/kg) and volumes of distribution (mouse 11.4, rat 9.2, dog 7.9, monkey 3.9 L/kg) following intravenous administration (mouse 1.0, rat 6.2, dog 0.5, monkey 0.5 μM/kg)^[2].