Design and Synthesis of α-Conotoxin GID Analogues as Selective α4β2 Nicotinic Acetylcholine Receptor Antagonists

The alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) is an important target for currently approved smoking cessation therapeutics. However, the development of highly selective alpha 4 beta 2 nAChR antagonists remains a significant challenge. alpha-Conotoxin GID is an antagonist of alpha 4 beta 2 nAChRs, though it is significantly more potent toward the alpha 3 beta 2 and alpha 7 subtypes. With the goal of obtaining further insights into alpha-conotoxin GID/nAChR interactions that could lead to the design of GID analogues with improved affinity for alpha 4 beta 2 nAChRs, we built a homology moel of the GID/alpha 4 beta 2 complex using an X-ray co-crystal structure of an alpha-conotoxin/acetylcholine binding protein (AChBP) complex. Several additional interactions that could potentially enhance the affinity of GID for alpha 4 beta 2 nAChRs were observed in our mode, which led to the design and synthesis of 22 GID analogues. Seven analogues displayed inhibitory activity toward alpha 4 beta 2 nAChRs that was comparable to GID. Significantly, both GID[A10S] and GID[V13I] demonstrated moderately improved selectivity toward alpha 4 beta 2 over alpha 3 beta 2 when compared with GID, while GID[V18N] exhibited no measurable inhibitory activity for the alpha 3 beta 2 subtype, yet retained inhibitory activity for alpha 4 beta 2. In this regard, GID[V18N] is the most alpha 4 beta 2 nAChR selective alpha-conotoxin analogue identified to date. (C) 2013 Wiley Periodicals, Inc.