Search for the pharamcophore of the K+ channel blocker, apamin

Article abstract of DOI:10.1016/0223-5234(91)90133-8

The suggestion that the arginine residues, ¹³Arg and ¹⁴Arg, in the octadecapeptide apamin 1 are critically important to its action in blocking Ca²⁺-dependent K⁺ channels (and hence part of the 'pharmacophore') has been investigated by examining small peptides containing Arg-Arg or Lys-Arg. Bisguanidine derivatives modelled on the Arg-Arg partial pharmacophore have also been synthesised and tested; in particular, N-(2-guanidinoethyl)-3[N¹-(2-guanidinoethyl)carbamoyl]-trans-propena mide 11 and its higher homologue 12. None of the compounds showed more than weak activity (K(i) > 10^-5 M) indicating that although the Arg-Arg fragment may be necessary, it is not a sufficient atom grouping for the pharmacophore.