NS 1738

NS 1738 (NSC 213859) is a novel positive allosteric modulator of the α7 nAChR, with respect to positive modulation of α7 nAChR (EC₅₀=3.4 μM in oocyte experiments). IC50 & Target: EC50: 3.4 μM (α7 nAChR, in oocyte experiments)^[1] In Vitro: NS 1738 acts by increasing the peak amplitude of acetylcholine (ACh)-evoked currents at all concentrations; thus, it increased the maximal efficacy of ACh. Plotting peak current amplitude against the logarithm of the NS 1738 concentration used for preincubation reveals a sigmoidal concentration-response relationship that is well fit by the Hill equation (EC₅₀=3.4 μM). Under similar experimental conditions, NS 1738 shows comparable efficacy and potency at the rat α7 nAChR (EC₅₀=3.9 μM)^[1]. In Vivo: To estimate the ability of NS 1738 to permeate the blood-brain barrier, rats are administered 10 mg/kg NS 1738 intraperitoneally. Peak brain concentrations are measured approximately 30 min after injection, and they amount to ~80 ng/mL (~200 nM) at this dose. The ratio between the amount of compound entering the brain and that in plasma is AUC_brain /AUC_plasma=0.50. The half-life in plasma is estimated to 42 min. Incubation of NS1738 with isolated liver microsomes in vitro indicates that approximately 60 and 75% of NS 1738 is metabolized via the cytochrome P450 system in mouse and rat, respectively, within 1 h. Adult rats administered NS 1738 at 10 and 30 mg/kg i.p. immediately following the initial exposure to a juvenile rat (T1) display significant decreases in the investigative duration of a subsequent exposure to the same juvenile (T2) 2 h later (T2/T1 ratio of 0.69±0.13 and 0.61±0.07, respectively)^[1].