Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on κ receptor selectivity and potency

Tyrosine1 and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at κ receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [d-Ala3]Dyn A(1−11)-NH2 (2) and [Ala3]Dyn A(1−11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central κ opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1−11)-NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for κ vs μ and κ vs δ receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1−11)-NH2 as well as the conformational changes they induce in ...