Synthese von 6‐Äthyl‐α‐ und 6‐Äthyl‐β‐jonon

Surber, W.; Schinz, H.

doi:10.1002/hlca.19540370427

Cited by 5 publications

(3 citation statements)

References 17 publications

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“…The required enone ( 5 ) was synthesized from methyl 2-ethyl-3-oxobutanoate according to previously described procedures (Scheme S2B). 57 …”

Section: Resultsmentioning

confidence: 99%

“…The required enone (5) was synthesized from methyl 2-ethyl-3oxobutanoate according to previously described procedures (Scheme S2B). 57 With the necessary building blocks in hand, we attempted the key proline-mediated step for formation of ring D. Initial experiments with crude β-carboline 4 treated with an excess of enone 5 in the presence of proline, afforded the desired ketones in moderate yield as a mixture of epimers 6 and 7. Importantly, we found that the major diastereomer 6 was obtained in high enantiomeric excess (ee), while the minor diastereomer 7 was obtained in much lower ee.…”

Section: Figures S1 S2 and S3mentioning

confidence: 99%

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Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

et al. 2016

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Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analog 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.

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“…The required enone ( 5 ) was synthesized from methyl 2-ethyl-3-oxobutanoate according to previously described procedures (Scheme S2B). 57 …”

Section: Resultsmentioning

confidence: 99%

Section: Figures S1 S2 and S3mentioning

confidence: 99%

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

et al. 2016

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“…A new group of antinicotine substances has been described by Surber (214); they antagonize the effects of nicotine without depressing gang lionic transmission or the response to other "nicotine-like" substances, such as dimethylphenylpiperazine. Their mode of action is not yet known.…”

Section: Ganglion -Blocking Substancesmentioning

confidence: 99%

Pharmacology of Autonomic Ganglia

Trendelenburg¹

1961

Annu. Rev. Pharmacol.

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Produits à odeur de violette. 56^e communication. Sur les acides α‐ et β‐cyclocitrylidène‐acétiques et quelques composés apparentés

Tribolet

Schinz

1954

Helvetica Chimica Acta

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Sur les acides aet /?-cyclocitrylidene-acbtiqyes et quelques compos6s apparent& par P. de Tribolet2) e t H. Schinz. (27 VIII 54) 56e communication'). W . G. Y o u n g , L. J. A n d r e w s & St. J . Cristo13) ainsi qu' E. E . R o y a W ) dbcrivent l'oxydation l'hypochlorite des ionones , ! ? et CI en acides C12Ef1802 correspondants. Dans le premier cas ces auteurs obtinrent un produit cristallin, dans le second une huile visqueuse5) qui ne fut pas analyske. Nous avons repris cette Btude pour 1'Btendre B d'autres produits plus compliques de la serie iononique6). Nous avons Bgalement effectuB la reaction avec la pseudo-ionone. Enfin nous avons r6alisB quelques transformations des acides C,,H1,O, en d'autres composBs de structure analogue. A. Essais h partir de la /I-ionone. L'acide b-cyclocitrylidhe-acBtique (11)') obteau dans nos essais montre, en accord avec E. E. Royals, F. 106O; spectre UV.: Amax 280 mpl log E = 3,95; absorption terminale B 220 mp, log E = 3'70.

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Synthese von 6‐Äthyl‐α‐ und 6‐Äthyl‐β‐jonon

Cited by 5 publications

References 17 publications

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Pharmacology of Autonomic Ganglia

Produits à odeur de violette. 56^e communication. Sur les acides α‐ et β‐cyclocitrylidène‐acétiques et quelques composés apparentés

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Synthese von 6‐Äthyl‐α‐ und 6‐Äthyl‐β‐jonon

Cited by 5 publications

References 17 publications

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Pharmacology of Autonomic Ganglia

Produits à odeur de violette. 56e communication. Sur les acides α‐ et β‐cyclocitrylidène‐acétiques et quelques composés apparentés

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Produits à odeur de violette. 56^e communication. Sur les acides α‐ et β‐cyclocitrylidène‐acétiques et quelques composés apparentés