PNU-120596

• CAT Number: I003767
• CAS Number: 501925-31-1
• Molecular Formula: C13H14ClN3O4
• Molecular Weight: 311.7
• Purity: ≥95%
• Target: AChR
• Solubility: DMSO ≥60mg/mL Water <1.2mg/mL Ethanol ≥1.2mg/mL
• Storage: 3 years -20C powder
• IC50: 0.2 uM (EC50) [1]
• InChIKey: CEIIEALEIHQDBX-UHFFFAOYSA-N

PNU-120596 (NSC 216666 ) is a potent and selective positive allosteric α7 nAChR modulator with an EC50 of 0.2 μM.IC50 value: 0.2 uM (EC50) [1]Target: α7in vitro: PNU-120596 increases agonist (Ach)-evoked calcium flux mediated by an engineered variant of the human α7 nAChR. PNU-120596 increases agonists (choline and ACh)-evoked currents mediated by wild-type receptors and also demonstrates a pronounced prolongation of the evoked response in the continued presence of agonist in Xenopus oocytes. PNU-120596 increases the channel mean open time ofα7 nAChRs but has no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increases the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect is suppressed by TTX, suggesting that PNU-120596 modulates the function of α7 nAChRs located on the somatodendritic membrane of hippocampal interneurons [1]. Besides the positive modulation to α7 nAChR, PNU-120596 induces a profound retardation of the kinetics of desensitization, raising the potential of Ca2+-induced toxicity through excessive stimulation of α7 nAChR [2]. PNU-120596 causes changes in cysteine accessibility at the inner beta sheet, transition zone and agonist binding site while binding to α7 nAChR. Binding sites for PNU-120596 are not in the agonist-binding sites and PNU-120596 enhances agonist-evoked gating of nicotinic receptors by eliciting conformational effects that are similar but nonidentical to the gating conformations promoted by Ach [3].in vivo: Systemic administration of PNU-120596 (1 mg/kg) to rats improves the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. [1] When administered prior to Carrageenan, 30 mg/kg PNU-1230596 significantly blunts mechanical hyperalgesia and weight bearing deficits for up to 4 hours. PNU-120596 attenuates the carrageenan-induced increase in levels of TNF-α and IL-6 within the hindpaw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by Carrageenan or CFA is also partially reversed by PNU-120596 [4].

Reference

1:An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors. Marotta CB, Lester HA, Dougherty DA.Chem Biol. 2015 Aug 20;22(8):1063-73. doi: 10.1016/j.chembiol.2015.06.018. Epub 2015 Jul 23. PMID: 26211363 Free PMC Article2:Mode of action of the positive modulator PNU-120596 on α7 nicotinic acetylcholine receptors. Szabo AK, Pesti K, Mike A, Vizi ES.Neuropharmacology. 2014 Jun;81:42-54. doi: 10.1016/j.neuropharm.2014.01.033. Epub 2014 Jan 31. PMID: 24486377 3:The dual effect of PNU-120596 on α7 nicotinic acetylcholine receptor channels. Kalappa BI, Uteshev VV.Eur J Pharmacol. 2013 Oct 15;718(1-3):226-34. doi: 10.1016/j.ejphar.2013.08.027. Epub 2013 Sep 11. PMID: 24036349 Free PMC Article4:Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. Callahan PM, Hutchings EJ, Kille NJ, Chapman JM, Terry AV Jr.Neuropharmacology. 2013 Apr;67:201-12. doi: 10.1016/j.neuropharm.2012.10.019. Epub 2012 Nov 17. PMID: 23168113 Free PMC Article5:The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat. Munro G, Hansen R, Erichsen H, Timmermann D, Christensen J, Hansen H.Br J Pharmacol. 2012 Sep;167(2):421-35. doi: 10.1111/j.1476-5381.2012.02003.x. PMID: 22536953 Free PMC Article6:Somatic integration of single ion channel responses of α7 nicotinic acetylcholine receptors enhanced by PNU-120596. Uteshev VV.PLoS One. 2012;7(3):e32951. doi: 10.1371/journal.pone.0032951. Epub 2012 Mar 30. PMID: 22479351 Free PMC Article7:Protective effect of PNU-120596, a selective alpha7 nicotinic acetylcholine receptor-positive allosteric modulator, on myocardial ischemia-reperfusion injury in rats. Li H, Zhang ZZ, Zhan J, He XH, Song XM, Wang YL.J Cardiovasc Pharmacol. 2012 Jun;59(6):507-13. doi: 10.1097/FJC.0b013e31824c86c3. PMID: 22343370 8:PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptors, reverses a sub-chronic phencyclidine-induced cognitive deficit in the attentional set-shifting task in female rats. McLean SL, Idris NF, Grayson B, Gendle DF, Mackie C, Lesage AS, Pemberton DJ, Neill JC.J Psychopharmacol. 2012 Sep;26(9):1265-70. doi: 10.1177/0269881111431747. Epub 2011 Dec 18. PMID: 22182741 9:Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states. Williams DK, Wang J, Papke RL.Mol Pharmacol. 2011 Dec;80(6):1013-32. doi: 10.1124/mol.111.074302. Epub 2011 Sep 1. PMID: 21885620 Free PMC Article10:Activation of functional α7-containing nAChRs in hippocampal CA1 pyramidal neurons by physiological levels of choline in the presence of PNU-120596. Kalappa BI, Gusev AG, Uteshev VV.PLoS One. 2010 Nov 12;5(11):e13964. doi: 10.1371/journal.pone.0013964. PMID: 21103043 Free PMC Article