NS 1738

NS1738 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).

Signaling Pathways >> Membrane Transporter/Ion Channel >> nAChR

Signaling Pathways >> Neuronal Signaling >> nAChR

Research Areas >> Neurological Disease

EC50: 3.4 μM (α7 nAChR, in oocyte experiments)[1]

NS1738 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 NS1738 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, NS1738 shows comparable efficacy and potency at the rat α7 nAChR (EC50=3.9 μM)[1].

To estimate the ability of NS1738 to permeate the blood-brain barrier, rats are administered 10 mg/kg NS1738 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 NS1738 is metabolized via the cytochrome P450 system in mouse and rat, respectively, within 1 h. Adult rats administered NS1738 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].

Preparations are performed at 0-4°C unless otherwise indicated. Cerebral cortices and hippocampi from male Wistar rats, weighing 150 to 250 g, are homogenized for 10 s in 15 ml of 20 mM HEPES buffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO4, and 2.5 mM CaCl2, pH 7.5, by using an Ultra-Turrax homogenizer. The tissue suspension is centrifuged at 27,000g for 10 min. The supernatant is discarded, and the pellet is washed twice by centrifugation at 27,000g for 10 min in 20 mL of fresh buffer, and the final pellet is resuspended in fresh buffer containing 0.01% bovine serum albumin (35 mL/g original tissue). The reaction mixture consists of 500 μL of homogenate, 25 μL of [3H]α-BgTx, and 25 μL of buffer or (–)-Nicotine (1 mM to define nonspecific binding), Saturation curves are obtained for the binding of 0.05 to 10 nM [3H]α-BgTx in the absence and presence of 10 μM NS1738. The binding at each concentration is determined using three samples for total and nonspecific binding, respectively. After an incubation time of 2 h at 37°C, the reaction is terminated by the addition of 5 mL of ice-cold HEPES buffer containing 0.05% polyethyleneimine, and the solution is poured directly onto GF/C glass fiber filters (presoaked in 0.1% polyethyleneimine for at least 0.5 h) under suction, and they are immediately washed with 2×5 mL of ice-cold buffer. The amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Protein concentration is measured[1].

Rats[1] Sprague-Dawley rats are used. Adult (2-4 months; 400-450 g) and juvenile (50-60 g) animals are allowed to acclimate to the test room for 90 to 120 min before starting. After acclimation, adult rats are placed alone in their respective test cages. After a brief habituation period (30 min), they are allowed to interact for 5 min with a juvenile rat (trial; T1). During the interactive trial, the adult exhibits investigative behaviors that include close following, grooming, and/or sniffing of the juvenile for as much as 40 to 50% of the trial duration. The time of the investigative interaction is recorded in seconds. The juvenile rat is then removed, and the adult rats are immediately administered varying doses of NS1738 (10 and 30 mg/kg NS-1738 i.p.) [prepared in 5% ethanol/95% hydroxypropyl-B-cyclodextrin (34% solution); 2.0 mL/kg i.p. ] or Nicotine (0.1 mg/kg i.p.), and then they are returned to their home cage. A second 5-min interactive trial (T2) is conducted 120 min later in the same test cage, and investigative behavior of the adult rat is again monitored and the time is recorded. Recognition ratios of time spent investing the familiar juvenile in T2 divided by time spent investigating the juvenile in T1 are calculated.

[1]. Timmermann DB, et al. An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J Pharmacol Exp Ther. 2007 Oct;323(1):294-307.

PNU 282987 | Carbachol | GTS-21 | Methyllycaconitine citrate | Monepantel | Hexamethonium bromide | PNU-120596 | Centrophenoxine hydrochloride | ZSET1446 | Aniracetam | Desformylflustrabromine hydrochloride | EVP-6124 (hydrochloride) | α-Lobeline Hydrochcloride | ABT 594 hydrochloride | Varenicline