Use of Synthetic Analogs for a Study on the Structure‐Activity Relationship of Apamin

Abstract

[Lys¹³, Lys¹⁴]Apamin, [Lys¹³]apamin and [Lys¹⁴]apamin, three structural analogs of the bee venom neurotoxin, have been obtained by solid-phase peptide synthesis while an attempt to obtain [Cit¹³]apamin failed, probably at the step of reoxidation of cysteines. After the chemical purity of these three derivatives had been assessed, further chemical modifications led to three new peptides: [Ac-Cys¹, Lys(Ac)⁴, Lys(Ac)¹³]apamin, [Ac-Cys¹, Lys(Ac)⁴, Lys(Ac)¹⁴]apamin and [Har⁴, Har¹³, Har¹⁴]apamin. These six analogs have been tested for their neurotoxicity, i.e. determination of LD₅₀ for mouse by subcutaneous injection. A lethal potency is observed only when the region 13–14 of the sequence contains a double positive charge. One arginyl residue is necessary for a high biological activity, while its location in position 13 or 14 is of minor importance. When homoarginine (Har) replaces arginyl residues the neurotoxicity is lowered.