Structure -: Activity relationship studies of spinorphin as a potent and selective human P2X3 receptor antagonist

Spinorphin, an endogenous antinociceptive peptide (LVVYPWT), showed potent and non-competitive antagonism at the ATP-activated human P2X(3) receptor (IC50 = 8.3 pM) in a two-electrode voltage clamp assay with recombinant human P2X(3) receptors expressed in Xenopus oocytes. Single alanine substitutions from 1st to 4th amino acids and the cyclic form of LVVYPWT sustained antagonistic properties at the human P2X(3) receptors, whereas the threonine to alanine substitution resulted in an enhancing effect of the agonistic activity.