Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

A. Potasiewicz, T. Kos, F. Ravazzini, G. Puia, H. R. Arias, P. Popik, Agnieszka Nikiforuk

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background and Purpose α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2). Experimental Approach The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg-1), DMXBA and A-582941 (0.3 and 1.0 mg·kg-1)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg-1) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg-1 (ASST) or A-582941: 0.1 mg·kg-1. Key Results PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC50 = 34 ± 3 μM and Emax = 225 ± 5 %. Conclusions and Implications Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders.

Original languageEnglish
Pages (from-to)5123-5135
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number21
DOIs
StatePublished - 1 Nov 2015
Externally publishedYes

Fingerprint

A-582941
Acrylamide
Nicotinic Receptors
Cognition
Drug Interactions
Ligands
Scopolamine Hydrobromide
pralidoxime
furan
3-(2,4-dimethoxybenzylidene)anabaseine
Injections

Cite this

Potasiewicz, A. ; Kos, T. ; Ravazzini, F. ; Puia, G. ; Arias, H. R. ; Popik, P. ; Nikiforuk, Agnieszka. / Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 21. pp. 5123-5135.
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title = "Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor",
abstract = "Background and Purpose α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2). Experimental Approach The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg-1), DMXBA and A-582941 (0.3 and 1.0 mg·kg-1)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg-1) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg-1 (ASST) or A-582941: 0.1 mg·kg-1. Key Results PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC50 = 34 ± 3 μM and Emax = 225 ± 5 {\%}. Conclusions and Implications Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders.",
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Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor. / Potasiewicz, A.; Kos, T.; Ravazzini, F.; Puia, G.; Arias, H. R.; Popik, P.; Nikiforuk, Agnieszka.

In: British Journal of Pharmacology, Vol. 172, No. 21, 01.11.2015, p. 5123-5135.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

AU - Potasiewicz, A.

AU - Kos, T.

AU - Ravazzini, F.

AU - Puia, G.

AU - Arias, H. R.

AU - Popik, P.

AU - Nikiforuk, Agnieszka

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Background and Purpose α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2). Experimental Approach The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg-1), DMXBA and A-582941 (0.3 and 1.0 mg·kg-1)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg-1) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg-1 (ASST) or A-582941: 0.1 mg·kg-1. Key Results PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC50 = 34 ± 3 μM and Emax = 225 ± 5 %. Conclusions and Implications Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders.

AB - Background and Purpose α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2). Experimental Approach The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg-1), DMXBA and A-582941 (0.3 and 1.0 mg·kg-1)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg-1) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg-1 (ASST) or A-582941: 0.1 mg·kg-1. Key Results PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC50 = 34 ± 3 μM and Emax = 225 ± 5 %. Conclusions and Implications Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders.

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