Synthesis and δ-Opioid Receptor Antagonist Activity of a Naltrindole Analogue with a Regioisomeric Indole Moiety

P. S. Portoghese; S. Ohkawa; S. T. Moe; A. E. Takemori

doi:10.1021/jm00038a019

Synthesis and δ-Opioid Receptor Antagonist Activity of a Naltrindole Analogue with a Regioisomeric Indole Moiety

P. S. Portoghese, S. Ohkawa, S. T. Moe, A. E. Takemori

Medicinal Chemistry

Research output: Contribution to journal › Comment/debate › peer-review

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Abstract

Indolomorphinans 2 and 3, in which the indole moiety is fused to the 7,8-position of the morphinan system, have been synthesized from dihydropseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorphinan 2 was found to be ~ 1/60th as potent as naltrindole 1 in the MVD and an agonist in the GPI preparation. A comparable difference in affinity between 1 and 2 was observed. The methyl analogue 3 was inactive in both preparations. The results of this study support the idea that the regio orientation of the indolic benzene moiety of 1 is optimal for δ-opioid receptor antagonist activity. It is proposed that the proper alignment of the benzene moiety with an address subsite on the δ receptor is critical for potent δ antagonist activity.

Original language	English (US)
Pages (from-to)	1886-1888
Number of pages	3
Journal	Journal of medicinal chemistry
Volume	37
Issue number	12
DOIs	https://doi.org/10.1021/jm00038a019
State	Published - Jun 1 1994

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title = "Synthesis and δ-Opioid Receptor Antagonist Activity of a Naltrindole Analogue with a Regioisomeric Indole Moiety",

abstract = "Indolomorphinans 2 and 3, in which the indole moiety is fused to the 7,8-position of the morphinan system, have been synthesized from dihydropseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorphinan 2 was found to be ~ 1/60th as potent as naltrindole 1 in the MVD and an agonist in the GPI preparation. A comparable difference in affinity between 1 and 2 was observed. The methyl analogue 3 was inactive in both preparations. The results of this study support the idea that the regio orientation of the indolic benzene moiety of 1 is optimal for δ-opioid receptor antagonist activity. It is proposed that the proper alignment of the benzene moiety with an address subsite on the δ receptor is critical for potent δ antagonist activity.",

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T1 - Synthesis and δ-Opioid Receptor Antagonist Activity of a Naltrindole Analogue with a Regioisomeric Indole Moiety

AU - Portoghese, P. S.

AU - Ohkawa, S.

AU - Moe, S. T.

AU - Takemori, A. E.

PY - 1994/6/1

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N2 - Indolomorphinans 2 and 3, in which the indole moiety is fused to the 7,8-position of the morphinan system, have been synthesized from dihydropseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorphinan 2 was found to be ~ 1/60th as potent as naltrindole 1 in the MVD and an agonist in the GPI preparation. A comparable difference in affinity between 1 and 2 was observed. The methyl analogue 3 was inactive in both preparations. The results of this study support the idea that the regio orientation of the indolic benzene moiety of 1 is optimal for δ-opioid receptor antagonist activity. It is proposed that the proper alignment of the benzene moiety with an address subsite on the δ receptor is critical for potent δ antagonist activity.

AB - Indolomorphinans 2 and 3, in which the indole moiety is fused to the 7,8-position of the morphinan system, have been synthesized from dihydropseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorphinan 2 was found to be ~ 1/60th as potent as naltrindole 1 in the MVD and an agonist in the GPI preparation. A comparable difference in affinity between 1 and 2 was observed. The methyl analogue 3 was inactive in both preparations. The results of this study support the idea that the regio orientation of the indolic benzene moiety of 1 is optimal for δ-opioid receptor antagonist activity. It is proposed that the proper alignment of the benzene moiety with an address subsite on the δ receptor is critical for potent δ antagonist activity.

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Synthesis and δ-Opioid Receptor Antagonist Activity of a Naltrindole Analogue with a Regioisomeric Indole Moiety

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