Kasheverov_2011_Mar.Drugs_9_1698

A series of 14 new analogs of alpha-conotoxin PnIA Conus pennaceus was synthesized and tested for binding to the human alpha7 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, single and multiple amino acid substitutions were introduced in alpha-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 alpha7 nAChR, as found in competition with radioiodinated alpha-bungarotoxin. That is why we prepared radioiodinated derivatives of these alpha-conotoxins, demonstrated their specific binding and found that among the tested synthetic analogs, most had almost 10-fold higher affinity in competition with radioactive alpha-conotoxins as compared to competition with radioactive alpha-bungarotoxin. Thus, radioiodinated alpha-conotoxins are a more sensitive tool for checking the activity of novel alpha-conotoxins and other compounds quickly dissociating from the receptor complexes.