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

Xin Li; Wenjun Xie; Xintong Wang; Zongze Huang; Xiling Bian; KeWei Wang; Qi Sun

doi:10.1016/j.bmcl.2019.05.046

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

Bioorg Med Chem Lett. 2019 Aug 1;29(15):1928-1933. doi: 10.1016/j.bmcl.2019.05.046. Epub 2019 May 22.

Authors

Xin Li¹, Wenjun Xie², Xintong Wang³, Zongze Huang¹, Xiling Bian³, KeWei Wang⁴, Qi Sun⁵

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
² State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
³ Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
⁴ Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266021, China. Electronic address: wangkw@qdu.edu.cn.
⁵ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: sunqi@bjmu.edu.cn.

PMID: 31153804
DOI: 10.1016/j.bmcl.2019.05.046

Abstract

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-HT_3A 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.

Keywords: Alzheimer’s disease; Cognitive impairment; Nicotinamide; Positive allosteric modulators; α7 nAChR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Humans
Nicotinic Agonists / pharmacology
Nicotinic Agonists / therapeutic use*
Structure-Activity Relationship
alpha7 Nicotinic Acetylcholine Receptor / drug effects*

Substances

Nicotinic Agonists
alpha7 Nicotinic Acetylcholine Receptor