Abstract
A series of 14 new analogs of α-conotoxin PnIA Conus pennaceus was synthesized and tested for binding to the human α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine-binding proteins (AChBP) Lymnaea stagnalis and Aplysia californica. Based on computer modeling and the X-ray structure of the A. californica AChBP complex with the PnIA[A10L, D14K] analog [1], single and multiple amino acid substitutions were introduced in α-conotoxin PnIA aimed at compounds of higher affinity and selectivity. Three analogs, PnIA[L5H], PnIA[A10L, D14K] and PnIA[L5R, A10L, D14R], have high affinities for AChBPs or α7 nAChR, as found in competition with radioiodinated α-bungarotoxin. That is why we prepared radioiodinated derivatives of these α-conotoxins, demonstrated their specific binding and found that among the tested synthetic analogs, most had almost 10-fold higher affinity in competition with radioactive α-conotoxins as compared to competition with radioactive α-bungarotoxin. Thus, radioiodinated α-conotoxins are a more sensitive tool for checking the activity of novel α-conotoxins and other compounds quickly dissociating from the receptor complexes.
Highlights
IntroductionIntroduction αConotoxins are at present the most precise tools for research on nicotinic acetylcholine receptors (nAChRs), mainly due to their relatively high specificity for different nAChR subtypes and small size, enabling solid-phase synthesis of α-conotoxins in large amounts (see, for example, reviews [2,3,4,5]).Involvement of distinct nAChR subtypes in muscle dystrophies, psychiatric, and neurodegenerative diseases [6,7,8] makes practical application of different cholinergic ligands crucial, including α-conotoxins as selective markers of the respective subtypes in normal state and pathologies, as well as for designing new drugs
Introduction αConotoxins are at present the most precise tools for research on nicotinic acetylcholine receptors, mainly due to their relatively high specificity for different nAChR subtypes and small size, enabling solid-phase synthesis of α-conotoxins in large amounts.Involvement of distinct nAChR subtypes in muscle dystrophies, psychiatric, and neurodegenerative diseases [6,7,8] makes practical application of different cholinergic ligands crucial, including α-conotoxins as selective markers of the respective subtypes in normal state and pathologies, as well as for designing new drugs
Computer modeling of α-conotoxin PnIA analogs and their docking to acetylcholine-binding proteins (AChBP) and nAChRs was performed using the X-ray structures of α-conotoxins PnIA and PnIB [25,26] and the techniques and programs earlier employed with different α-conotoxins [1,27,28] and α-neurotoxins [29]
Summary
Introduction αConotoxins are at present the most precise tools for research on nicotinic acetylcholine receptors (nAChRs), mainly due to their relatively high specificity for different nAChR subtypes and small size, enabling solid-phase synthesis of α-conotoxins in large amounts (see, for example, reviews [2,3,4,5]).Involvement of distinct nAChR subtypes in muscle dystrophies, psychiatric, and neurodegenerative diseases [6,7,8] makes practical application of different cholinergic ligands crucial, including α-conotoxins as selective markers of the respective subtypes in normal state and pathologies, as well as for designing new drugs. We tried to make new α-conotoxin analogs of higher affinity and selectivity to a homooligomeric α7 nAChR. This subtype is one of the best presented, especially in the brain, and appears to play an important role in Alzheimer’s disease [12,13]. Among α-conotoxins, for some time such a role was ascribed to α-conotoxin ImI [14,15] but later its binding to some other subtypes was registered [16,17] Another candidate was α-conotoxin PnIA, a α3β2 nAChR blocker, where a single
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