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4?-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4?-methyl-5-(3-hydroxyphenyl)morphan pure antagonist.

ABSTRACT: In previous studies we reported that addition of 7?-acylamino groups to N-phenylpropyl-4?-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7?-amino (5a), 7?-alkylamino (5b-e), or 7?-dialkylamino (5f-h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7?-amino and 7?-methylamino analogues were full agonists at the ? and ? receptors and antagonists at the ? receptor. The 7?-cyclopropylmethylamino analogue 5h was a full agonist at the ? receptor with weaker agonist activity at the ? and ? receptors. Whereas the addition of a 7?-acylamino group to the pure nonselective opioid receptor antagonist N-phenylpropyl-4?-methyl-5-(3-hydroxyphenyl)morphan (4) led to ? selective pure opioid receptor antagonist, the addition of a 7?-amino, 7?-alkylamino, or 7?-dialkylamino group to 4 leads to opioid ligands that are largely ? or ? agonist with mixed agonist/antagonist properties.

SUBMITTER: Carroll FI

PROVIDER: S-EPMC3893112 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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4β-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4β-methyl-5-(3-hydroxyphenyl)morphan pure antagonist.

Carroll F Ivy FI Gichinga Moses G MG Williams John D JD Vardy Eyal E Roth Bryan L BL Mascarella S Wayne SW Thomas James B JB Navarro Hernán A HA

Journal of medicinal chemistry 20131105 21

In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b-e), or 7α-dialkylamino (5f-h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ re ...[more]

PMID: 24144404

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Project description:Scorpion β-toxin 4 from Centruroides suffusus suffusus (Css4) enhances the activation of voltage-gated sodium channels through a voltage sensor trapping mechanism by binding the activated state of the voltage sensor in domain II and stabilizing it in its activated conformation. Here we describe the antagonist and partial agonist properties of a mutant derivative of this toxin. Substitution of seven different amino acid residues for Glu(15) in Css4 yielded toxin derivatives with both increased and decreased affinities for binding to neurotoxin receptor site 4 on sodium channels. Css4(E15R) is unique among this set of mutants in that it retained nearly normal binding affinity but lost its functional activity for modification of sodium channel gating in our standard electrophysiological assay for voltage sensor trapping. More detailed analysis of the functional effects of Css4(E15R) revealed weak voltage sensor trapping activity, which was very rapidly reversed upon repolarization and therefore was not observed in our standard assay of toxin effects. This partial agonist activity of Css4(E15R) is observed clearly in voltage sensor trapping assays with brief (5 ms) repolarization between the conditioning prepulse and the test pulse. The effects of Css4(E15R) are fit well by a three-step model of toxin action involving concentration-dependent toxin binding to its receptor site followed by depolarization-dependent activation of the voltage sensor and subsequent voltage sensor trapping. Because it is a partial agonist with much reduced efficacy for voltage sensor trapping, Css4(E15R) can antagonize the effects of wild-type Css4 on sodium channel activation and can prevent paralysis by Css4 when injected into mice. Our results define the first partial agonist and antagonist activities for scorpion toxins and open new avenues of research toward better understanding of the structure-function relationships for toxin action on sodium channel voltage sensors and toward potential toxin-based therapeutics to prevent lethality from scorpion envenomation.

Dataset Information

4?-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4?-methyl-5-(3-hydroxyphenyl)morphan pure antagonist.

Publications

4β-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4β-methyl-5-(3-hydroxyphenyl)morphan pure antagonist.

Similar Datasets

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