Nonequilibrium Opioid Antagonist Activity of 6,14-Dideoxynaltrexone Derivatives

J. W. Schoenecker; A. E. Takemori; P. S. Portoghese

doi:10.1021/jm00389a014

Nonequilibrium Opioid Antagonist Activity of 6,14-Dideoxynaltrexone Derivatives

J. W. Schoenecker, A. E. Takemori, P. S. Portoghese

Medicinal Chemistry

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Abstract

A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3–5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-β-funaltrexamine (14-deoxy-β-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of β-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.

Original language	English (US)
Pages (from-to)	1040-1044
Number of pages	5
Journal	Journal of medicinal chemistry
Volume	30
Issue number	6
DOIs	https://doi.org/10.1021/jm00389a014
State	Published - Jun 1 1987

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abstract = "A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3–5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-β-funaltrexamine (14-deoxy-β-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of β-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.",

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T1 - Nonequilibrium Opioid Antagonist Activity of 6,14-Dideoxynaltrexone Derivatives

AU - Schoenecker, J. W.

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AU - Portoghese, P. S.

PY - 1987/6/1

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N2 - A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3–5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-β-funaltrexamine (14-deoxy-β-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of β-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.

AB - A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3–5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-β-funaltrexamine (14-deoxy-β-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of β-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.

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Nonequilibrium Opioid Antagonist Activity of 6,14-Dideoxynaltrexone Derivatives

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