Dynorphin A-(1-13)-Tyr14-Leu15-Phe16-Asn17-Gly18-Pro19 : a potent and selective kappa opioid peptide

Abstract

Dynorphin A-(1-13)-Tyr14-Leu15-Phe16-Asn17-Gly18-Pro19+ ++ (dynorphin Ia: a peptide derived from the structure of adrenal dynorphin I) was synthesized by the solid-phase procedure. The product was purified and compared with dynorphin A-(1-13) and [D-Pro10]dynorphin A-(1-11) for its ability to inhibit the electrically evoked contractions of the guinea pig ileum (GPI) and mouse vas deferens (MVD) and to compete with the binding of [3H]ethylketocyclazocine (kappa ligand), [3H][D-Ala2,MePhe4,Glyol5]enkephalin (mu ligand) and [3H][D-Ser2,Thr6]Leu-enkephalin (delta ligand) to membrane preparations of the guinea pig cerebellum or rat brain. Additionally, the antinociceptive effects of the synthetic peptide were assessed in rat paw-pressure and tail-flick tests. In the GPI, dynorphin Ia possessed a relative potency (IC50 0.5 nM) that was comparable to that of [D-Pro10]dynorphin A-(1-11) (IC50 0.5 nM) or dynorphin A-(1-13) (IC50 0.7 nM). In the delta specific MVD assay, dynorphin Ia displayed a reduced potency (IC50 235 nM) as compared with that of dynorphin A-(1-13) (IC50 20 nM) or [D-Pro10]dynorphin A-(1-11) (IC50 46 nM). The affinity of dynorphin Ia for the kappa site in the guinea pig cerebellum (Ki 0.25 nM) was comparable to those of dynorphin A-(1-13) (Ki 0.11 nM) and [D-Pro10]dynorphin A-(1-11) (Ki 0.10 nM). However, the peptide possessed reduced affinities for the mu (Ki 6.7 nM) and delta (Ki 71 nM) opioid receptors as compared with [D-Pro10]dynorphin A-(1-11) (Ki 1.7 and 1.5 nM) an dynorphin A-(1-13) (Ki 0.5 and 4.4 nM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)