Design and synthesis of α-conotoxin GID analogues as selective α4β2 nicotinic acetylcholine receptor antagonists.
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.
['Banerjee|Jayati|J|', 'Yongye|Austin B|AB|', 'Chang|Yi-Pin|YP|', 'Gyanda|Reena|R|', 'Medina-Franco|José L|JL|', 'Armishaw|Christopher J|CJ|']
D000595:Amino Acid Sequence D000818:Animals D001665:Binding Sites D020916:Conotoxins D015195:Drug Design D057809:HEK293 Cells D006801:Humans D008958:Models, Molecular D008969:Molecular Sequence Data D018733:Nicotinic Antagonists D051381:Rats D011978:Receptors, Nicotinic D014162:Transfection
α-conotoxin nicotinic acetylcholine receptors homology modeling acetylcholine binding protein