3610-35-3Relevant articles and documents
NITRATED PSILOCYBIN DERIVATIVES AND USE THEREOF FOR MODULATING 5-HT2A RECEPTOR AND FOR TREATING A PSYCHIATRIC DISORDER
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Paragraph 00101; 00328, (2022/03/22)
Disclosed are nitrated psilocybin compounds of formula (I), wherein at least one of R2, R4, R5, R6, or R7, is a nitro group, and wherein each non-nitrated R2, R5, R6, or R7, is a hydrogen atom, an alkyl, O-alkyl or O-aryl group, wherein R4 when it is not nitrated is a hydrogen atom, an alkyl, O-alkyl or O-aryl group, a hydroxy group, or a phosphate group, and wherein R3a, and R3b, are a hydrogen atom, an alkyl group, an aryl group, or an acyl group, pharmaceutical formulations containing the same. The nitrated psilocybin compounds of formula (I) may be chemically synthesized or biochemically synthesized in host cells. The nitrated compounds of formula (I) may be used for modulating 5-HT2A receptor, and for treating a psychiatric disorder in a subject.
Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators
Kruegel, Andrew C.,Gassaway, Madalee M.,Kapoor, Abhijeet,Váradi, András,Majumdar, Susruta,Filizola, Marta,Javitch, Jonathan A.,Sames, Dalibor
, p. 6754 - 6764 (2016/06/14)
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 human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analogue 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.
Alpha-ethyltryptamines as dual dopamine-serotonin releasers
Blough, Bruce E.,Landavazo, Antonio,Partilla, John S.,Decker, Ann M.,Page, Kevin M.,Baumann, Michael H.,Rothman, Richard B.
supporting information, p. 4754 - 4758 (2015/01/09)
The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT2A) receptor agonist activity of a series of substituted tryptamines are reported. Three compounds, 7b, (+)-7d and 7f, were found to be potent dual DA/5-HT releasers and were >10-fold less potent as NE releasers. Additionally, these compounds had different activity profiles at the 5-HT2Areceptor. The unique combination of dual DA/5-HT releasing activity and 5-HT2Areceptor activity suggests that these compounds could represent a new class of neurotransmitter releasers with therapeutic potential.
