Journal
ACS CHEMICAL NEUROSCIENCE
Volume 3, Issue 9, Pages 682-692Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cn300035f
Keywords
Negative allosteric modulator (NAM); neuronal nicotinic acetylcholine receptors (nAChRs); alpha 4 beta 2; site-directed mutagenesis; structure-activity relationships; nicotine
Funding
- National Institutes of Health National Institute on Drug Abuse [DA029433]
- National Institutes of Health National Institute on Drug Abuse Diversity Supplement
- American Foundation for Pharmaceutical Education
- Ohio Supercomputer Center
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Neuronal nicotinic receptors (nAChRs) have been implicated in several diseases and disorders such as autism spectrum disorders, Alzheimer's disease, Parkinson's disease, epilepsy, and nicotine addiction. To understand the role of nAChRs in these conditions, it would be beneficial to have selective molecules that target specific nAChRs in vitro and in vivo. Our laboratory has previously identified a novel allosteric site on human alpha 4 beta 2 nAChRs using a series of computational and in vitro approaches. At this site, we have identified negative allosteric modulators that selectively inhibit human alpha 4 beta 2 nAChRs, a subtype implicated in nicotine addiction. This study characterizes the allosteric site via site-directed mutagenesis. Three amino acids (Phe118, Glu60, and Thr58) on the beta 2 subunit were shown to participate in the inhibitory properties of the selective antagonist KAB-18 and provided insights into its antagonism of human alpha 4 beta 2 nAChRs. SAR studies with KAB-18 analogues and various mutant alpha 4 beta 2 nAChRs also provided information concerning how different physiochemical features influence the inhibition of nAChRs through this allosteric site. Together, these studies identify the amino acids that contribute to the selective antagonism of human alpha 4 beta 2 nAChRs at this allosteric site. Finally, these studies define the physiochemical features of ligands that influence interaction with specific amino acids in this allosteric site.
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