Synthesis and κ-Opioid Antagonist Selectivity of a Norbinaltorphimine Congener. Identification of the Address Moiety Required for κ-Antagonist Activity

Chia En Lin; Akira E. Takemori; Philip S. Portoghese

doi:10.1021/jm00068a020

Synthesis and κ-Opioid Antagonist Selectivity of a Norbinaltorphimine Congener. Identification of the Address Moiety Required for κ-Antagonist Activity

Chia En Lin, Akira E. Takemori, Philip S. Portoghese

Medicinal Chemistry

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Abstract

Compound 2, which represents a structurally simplified congener of norbinaltorphimine 1a, was synthesized in order to evaluate the role of its second basic nitrogen in conferring κ-opioid receptor antagonist selectivity. Congener 2 was found to be at least twice as selective as la as a κ antagonist, while its N-carbobenzoxy derivative (3) was inactive at κ-receptors. This study establishes the importance of the second basic nitrogen of la for κ-receptor recognition. It is proposed that this basic group mimics the guanidinium moiety of Arg⁷, which may be the key κ-address component of dynorphin.

Original language	English (US)
Pages (from-to)	2412-2415
Number of pages	4
Journal	Journal of medicinal chemistry
Volume	36
Issue number	16
DOIs	https://doi.org/10.1021/jm00068a020
State	Published - Jan 1 1993

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title = "Synthesis and κ-Opioid Antagonist Selectivity of a Norbinaltorphimine Congener. Identification of the Address Moiety Required for κ-Antagonist Activity",

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AB - Compound 2, which represents a structurally simplified congener of norbinaltorphimine 1a, was synthesized in order to evaluate the role of its second basic nitrogen in conferring κ-opioid receptor antagonist selectivity. Congener 2 was found to be at least twice as selective as la as a κ antagonist, while its N-carbobenzoxy derivative (3) was inactive at κ-receptors. This study establishes the importance of the second basic nitrogen of la for κ-receptor recognition. It is proposed that this basic group mimics the guanidinium moiety of Arg7, which may be the key κ-address component of dynorphin.

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Synthesis and κ-Opioid Antagonist Selectivity of a Norbinaltorphimine Congener. Identification of the Address Moiety Required for κ-Antagonist Activity

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