Chemical conversion of nicotinamide into type I positive allosteric modulator of α7 nAChRs

[Display omitted] Structural modifications of nicotinamide, a form of vitamin B3, gave rise to a series of compounds (8aa–8ce) that exhibit activities as type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus oocytes in two-electrode voltage clamp assay. The compound 8ai...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (15), p.1928-1933
Main Authors: Li, Xin, Xie, Wenjun, Wang, Xintong, Huang, Zongze, Bian, Xiling, Wang, KeWei, Sun, Qi
Format: Article
Language:English
Subjects:
Alzheimer’s disease
Cognitive impairment
Nicotinamide
Positive allosteric modulators
α7 nAChR
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Summary:[Display omitted] Structural modifications of nicotinamide, a form of vitamin B3, gave rise to a series of compounds (8aa–8ce) that exhibit activities as type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus oocytes in two-electrode voltage clamp assay. The compound 8ai was a potent and efficacious PAM with an EC50 = 3.34 ± 1.13 μM and the maximum activation effect of α7 current over 1474 ± 246% in the presence of acetylcholine (100 μM). It is highly specific to α7 nAChR over other subtypes of nAChR and 5-HT3A receptors. The structure–activity relationship analysis identified a key skeleton of nicotinamide nucleus critical for biological activity. Taken together, the 8ai as a type I PAM of α7 nAChR may be beneficial for improvement of cognitive deficit.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.05.046