Irreversible blockade of the kappa-receptor by a newly synthesized dynorphin derivative containing a 3-nitro-2-pyridinesulfenyl group.
The interactions of the dynorphin derivative containing a 3-nitro-2-pyridinesulfenyl group (dynorphin derivative) with kappa-receptors were studied. The dynorphin derivative inhibited, in a concentration-dependent manner, the twitch response to electrical stimulation of the longitudinal muscle of the guinea-pig ileum which contains both mu- and kappa-receptors. It also inhibited the twitch response to electrical stimulation of the rabbit vas deferens, reported to contain only kappa-receptors; its pD2 value was 11.57 +/- 0.09, suggesting that the agonistic activity of the dynorphin derivative is mainly mediated through kappa-receptors. The KD and Bmax values of [3H]U-69593 were calculated from a Scatchard plot of the specific binding. After a 30 min treatment with 10(-5) M of this dynorphin derivative, the KD value did not alter but the Bmax value decreased. However, this decrease recovered after treatment with 2 x 10(-3) M of dithiothreitol. These results suggest that the dynorphin derivative binds to kappa-receptors through the disulfide bound. The dissociation constant of nalorphine-7,8-oxide (nalorphine-epoxide) was determined according to the method of Furchgott, by irreversibly binding a fraction of the kappa-receptors with the dynorphin derivative. The negative logarithms of the dissociation constants (pKA values) for nalorphine-epoxide did not differ in the guinea-pig ileum and rabbit vas deferens, suggesting that the kappa-receptors in the two preparations are identical. However, the pD2 value and efficacy for nalorphine-epoxide in the guinea-pig ileum were significantly greater than those in the rabbit vas deferens. These results indicate that the kappa-receptor reserve in the longitudinal muscle of the guinea-pig ileum is greater than in the rabbit vas deferens. It is thought that the dynorphin derivative, containing a 3-nitro-2-pyridinesulfenyl group, is useful to clarify the kappa-receptor mechanisms.
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
K
K
Koike
I
I
Takayanagi
Y
Y
Hirakura
R
R
Matsueda
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D004399:Dynorphins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D009292:Narcotic Antagonists; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D012044:Regression Analysis; D014649:Vas Deferens / Q000187:drug effects
D009292:Narcotic Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C074706:3-nitro-2-pyridinesulfenyl dynorphin derivative; D004399:Dynorphins