Description
NS 1738 is a positive allosteric modulator of the α7-containing neuronal nicotinic acetylcholine receptors (nAChRs). When applied in the presence of ACh, NS 1738 increases the peak amplitude of the current flowing through α7-containing nAChRs (EC
50 = 3.4 μM). NS 1738 displays no substantial activity for α4β2-, α3β3-, and α1-containing receptors. It is modestly brain-penetrant and counteracts (-)-scopolamine-induced deficit in acquisition of a water-maze learning task in rats. NS 1738 also improves performance in the rat social recognition test. NS 1738 is used to selectively evaluate the role of α7-containing nAChRs in signaling pathways.
Uses
NS 1738 is a selective a7 nAchR allosteric modulator.
Biological Activity
Selective positive allosteric modulator of α 7 nicotinic acetylcholine receptors. Exhibits no substantial activity for α 4 β 2, α 3 β 3 and α 1-containing receptors. Displays cognitive-enhancing properties in vivo .
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 AUCbrain /AUCplasma=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].
References
[1] DANIEL B TIMMERMANN. An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.[J]. Journal of Pharmacology and Experimental Therapeutics, 2007, 323 1: 294-307. DOI:
10.1124/jpet.107.120436[2] QING CHENG Jerrel L Y. Presynaptic α7 nicotinic acetylcholine receptors enhance hippocampal mossy fiber glutamatergic transmission via PKA activation.[J]. Journal of Neuroscience, 2014: 124-133. DOI:
10.1523/jneurosci.2973-13.2014[3] KELEN FREITAS M I D F Ivy Carroll. The antinociceptive effects of nicotinic receptors α7-positive allosteric modulators in murine acute and tonic pain models.[J]. Journal of Pharmacology and Experimental Therapeutics, 2013, 344 1: 264-275. DOI:
10.1124/jpet.112.197871
