Potent and selective indolomorphinan antagonists of the kappa-opioid receptor

William C. Stevens, Robert M. Jones, Govindan Subramanian, Thomas G. Metzger, David M. Ferguson, Philip S. Portoghese

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

The indole moiety in the delta-opioid antagonist, naltrindole (2, NTI), was employed as a scaffold to hold an 'address' for interaction with the kappa-opioid receptor. The attachment of the address to the 5'-position of the indole moiety was based on superposition of NTI upon the kappa antagonist, norbinaltorphimine (1, norBNI). A variety of cationic groups were employed as a kappa address in an effort to investigate its interaction with the anionic address subsite, Glu297, on the kappa receptor. Some of the groups that were employed for this purpose were amines, amidines, guanidines, and quaternary ammonium. Members of the series were found to have a varying degree of kappa antagonist potency and kappa selectivity when tested in smooth muscle preparations. The 5'-guanidine derivative 12a (GNTI) was the most potent member of the series and had the highest kappa selectivity ratio. GNTI was 2 times more potent and 6-10-fold more selective than norBNI (1). In general, the order of potency in the series was: guanidines < amidines ~ quaternary ammonium > amines. The kappa antagonist potency appeared to be a function of a combination of the pK(a) and distance constraint of the cationic substituent of the ligand. Receptor binding studies were qualitatively in agreement with the pharmacological data. Molecular modeling studies on 12a suggested that the protonated N-17 and guanidinium groups of GNTI are associated with Asp138 (TM3) and Glu297 (TM6), respectively, while the phenolic hydroxyl may be involved in donor - acceptor interactions with the imidazole ring of His291. It was concluded that the basis for the high kappa selectivity of GNTI is related both to association with the nonconserved Glu297 residue and to unfavorable interactions with an equivalent position in mu- and delta-opioid receptors.

Original languageEnglish (US)
Pages (from-to)2759-2769
Number of pages11
JournalJournal of Medicinal Chemistry
Volume43
Issue number14
DOIs
StatePublished - Jul 13 2000

Fingerprint

kappa Opioid Receptor
Guanidines
naltrindole
Guanidine
Amines
Amidines
delta Opioid Receptor
Narcotic Antagonists
mu Opioid Receptor
Ammonium Compounds
Hydroxyl Radical
Smooth Muscle
Pharmacology
Ligands
norbinaltorphimine
indole

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Potent and selective indolomorphinan antagonists of the kappa-opioid receptor. / Stevens, William C.; Jones, Robert M.; Subramanian, Govindan; Metzger, Thomas G.; Ferguson, David M.; Portoghese, Philip S.

In: Journal of Medicinal Chemistry, Vol. 43, No. 14, 13.07.2000, p. 2759-2769.

Research output: Contribution to journalArticle

Stevens, William C. ; Jones, Robert M. ; Subramanian, Govindan ; Metzger, Thomas G. ; Ferguson, David M. ; Portoghese, Philip S. / Potent and selective indolomorphinan antagonists of the kappa-opioid receptor. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 14. pp. 2759-2769.
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AU - Portoghese, Philip S.

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