Dynorphin A-(1-13)-Tyr14-Leu15-Phe16-Asn17-Gly18-Pro19 : a potent and selective kappa opioid peptide.
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)
Martinka
G P
GP
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ont., Canada.
Jhamandas
K
K
Sabourin
L
L
Lapierre
C
C
Lemaire
S
S
D000595:Amino Acid Sequence; D000818:Animals; D004399:Dynorphins / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016314:Ethylketocyclazocine / Q000378:metabolism; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa
D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C070405:dynorphin A (1-13), Tyr(14)-Leu(15)-Phe(16)-Asn(17)-Gly(18)-Pro(19)-; D016314:Ethylketocyclazocine; D004399:Dynorphins