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Design and synthesis of α‐conotoxin GID analogues as selective α4β2 nicotinic acetylcholine receptor antagonists
Author(s) -
Banerjee Jayati,
Yongye Austin B.,
Chang YiPin,
Gyanda Reena,
MedinaFranco José L.,
Armishaw Christopher J.
Publication year - 2014
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22413
Subject(s) - chemistry , nicotinic acetylcholine receptor , acetylcholine receptor , nicotinic agonist , antagonist , inhibitory postsynaptic potential , nicotinic antagonist , acetylcholine , stereochemistry , conotoxin , pharmacology , receptor , biochemistry , neuroscience , psychology , medicine , peptide
The α4β2 nicotinic acetylcholine receptor (nAChR) is an important target for currently approved smoking cessation therapeutics. However, the development of highly selective α4β2 nAChR antagonists remains a significant challenge. α‐Conotoxin GID is an antagonist of α4β2 nAChRs, though it is significantly more potent toward the α3β2 and α7 subtypes. With the goal of obtaining further insights into α‐conotoxin GID/nAChR interactions that could lead to the design of GID analogues with improved affinity for α4β2 nAChRs, we built a homology model of the GID/α4β2 complex using an X‐ray co‐crystal structure of an α‐conotoxin/acetylcholine binding protein (AChBP) complex. Several additional interactions that could potentially enhance the affinity of GID for α4β2 nAChRs were observed in our model, which led to the design and synthesis of 22 GID analogues. Seven analogues displayed inhibitory activity toward α4β2 nAChRs that was comparable to GID. Significantly, both GID[A10S] and GID[V13I] demonstrated moderately improved selectivity toward α4β2 over α3β2 when compared with GID, while GID[V18N] exhibited no measurable inhibitory activity for the α3β2 subtype, yet retained inhibitory activity for α4β2. In this regard, GID[V18N] is the most α4β2 nAChR selective α‐conotoxin analogue identified to date. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 78–87, 2014.