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Int J Mol Sci
2021 Jan 19;222:. doi: 10.3390/ijms22020973.
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Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators.
Ximenis M, Mulet J, Sala S, Sala F, Criado M, González-Muñiz R, Pérez de Vega MJ.
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The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.
RTI2018-097189-B-C22 Spanish Ministerio de Ciencia, Innovación y Universidades (MICIU-FEDER), 2019E030 CSIC, BFU2008-02160 Spanish Ministerio de Ciencia, Innovación y Universidades (MICIU-FEDER), SAF2011-22802 to SS Spanish Ministerio de Ciencia e Innovación
Figure 1. Characterization of curcumin (12) and two curcuminoids (compounds 13 and 14). (a–c) Ionic currents recorded in representative oocytes expressing human α7 nAChRs. Currents were evoked by 600 ms applications of ACh 200 μM in the absence (continuous line) and in the presence (dotted line) of 20 μM of 12 (panel (a)) or 10 μM of 13 (panel (b)) and 14 (panel (c)). All currents were recorded at a holding potential of –80 mV. (d) Concentration–response relationships for the potentiating effect of 12, 13, and 14 co-applied with ACh 200 μM. Continuous lines represent the fit to the Hill equation. Limited solubility of these compounds, especially 12 and 14, hindered the use of higher concentrations in order to adequately complete the curves, so that the following values should be considered with caution. Thus, maximal potentiating effects were estimated as 11 ± 3-, 5.5 ± 0.3-, and 5.5 ± 1.0-fold for compounds 12, 13, and 14, respectively. The EC50 values were 85 ± 35, 4.9 ± 1.0, and 6.9 ± 3.1 μM for 12, 13, and 14, respectively. (e) Concentration–response curves of peak currents elicited by ACh in control conditions or in the presence of 3 μM 13. Data have been normalized to the peak current obtained in control conditions with 1 mM ACh. Lines are fit to the Hill equation with parameters (Imax, EC50, nH): control (1.25, 176 μM, 1.25), 13 (2.70, 57 μM, 2.36). Data were taken from 3–7 oocytes from at least 2 donors.
Scheme 1. Synthesis of symmetrically substituted (17) and asymmetrically substituted (21, 22) curcumin derivatives.
Scheme 2. Synthesis of tetrahydrocurcumins 23-25.
Figure 2. Characterization of compound 23. (a) Ionic currents recorded in representative oocytes expressing human α7 nAChRs. Currents were evoked by 600 ms applications of ACh 200 μM in the absence (continuous line) and in the presence (dotted line) of 10 μM of 23. All currents were recorded at a holding potential of −80 mV. (b) Concentration–response relationship for the potentiating effect of 23 co-applied with ACh 200 μM. Continuous line represents the fit to the Hill equation. Thus, maximal potentiating effect was estimated as 2.7 ± 0.3-fold, and the EC50 value was 0.44 ± 0.28 μM. Data are taken from 3–7 oocytes from at least 2 donors.
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