Probing the effects of residues located outside the agonist binding site on drug-receptor selectivity in the nicotinic receptor.

ABSTRACT: The nicotinic acetylcholine receptors (nAChRs) are a family of closely related but pharmacologically distinct neurotransmitter-gated ion channels. They are therapeutic targets for a wide range of neurological disorders, and a key issue in drug development is selective targeting among the more than 20 subtypes of nAChRs that are known. The present work evaluates a proposed hydrogen bonding interaction involving a residue known as the "loop B glycine" that distinguishes receptors that are highly responsive to ACh and nicotine from those that are much less so. We have performed structure-function studies on the loop B site, including unnatural amino acid mutagenesis, in three different nAChR subtypes and found that the correlation between agonist potency and this residue is strong. Low potenc

SUBMITTER: Puskar NL 

PROVIDER: S-EPMC3356501 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature