Transformation of a κ-opioid receptor antagonist to a κ-agonist by transfer of a guanidinium group from the 5′- to 6′-position of naltrindole

S. Kumar Sharma, R. M. Jones, T. G. Metzger, D. M. Ferguson, P. S. Portoghese

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The importance of the indole scaffold of GNTI 3 in directing its address (5′-guanidinium group) to associate with the Glu297 residue of the κ-opioid receptor was investigated by the synthesis and biological evaluation of its 4′- (4a), 6′- (4b), and 7′- (4c) regioisomers. The finding that only the 5′-regioisomer (GNTI) possessed potent κ-opioid antagonist activity and high affinity at κ-receptors illustrates the importance of the 5′-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent κ-antagonist activity. The discovery that the 6′-regioisomer of GNTI was a potent κ-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6′-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the κ-receptor involves a conformational change of TM6. We propose that association of the 6′-guanidinium group of 4b with Glu297 promotes axial rotational motion of transmembrane helix VI which leads to receptor activation via a conformational change of inner loop 3.

Original languageEnglish (US)
Pages (from-to)2073-2079
Number of pages7
JournalJournal of Medicinal Chemistry
Volume44
Issue number13
DOIs
StatePublished - Jun 21 2001

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naltrindole
Narcotic Antagonists
Guanidine
Opioid Receptors
Site-Directed Mutagenesis

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Transformation of a κ-opioid receptor antagonist to a κ-agonist by transfer of a guanidinium group from the 5′- to 6′-position of naltrindole. / Kumar Sharma, S.; Jones, R. M.; Metzger, T. G.; Ferguson, D. M.; Portoghese, P. S.

In: Journal of Medicinal Chemistry, Vol. 44, No. 13, 21.06.2001, p. 2073-2079.

Research output: Contribution to journalArticle

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abstract = "The importance of the indole scaffold of GNTI 3 in directing its address (5′-guanidinium group) to associate with the Glu297 residue of the κ-opioid receptor was investigated by the synthesis and biological evaluation of its 4′- (4a), 6′- (4b), and 7′- (4c) regioisomers. The finding that only the 5′-regioisomer (GNTI) possessed potent κ-opioid antagonist activity and high affinity at κ-receptors illustrates the importance of the 5′-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent κ-antagonist activity. The discovery that the 6′-regioisomer of GNTI was a potent κ-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6′-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the κ-receptor involves a conformational change of TM6. We propose that association of the 6′-guanidinium group of 4b with Glu297 promotes axial rotational motion of transmembrane helix VI which leads to receptor activation via a conformational change of inner loop 3.",
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