ChemInform Abstract: Chemoenzymatic Synthesis and Cannabinoid Activity of a New Diazabicyclic Amide of Phenylacetylricinoleic Acid (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2010
Endocannabinoids (eCBs) are endogenous neuromodulators of synaptic transmission. Their dysfunction may cause debilitating disorders of diverse clinical manifestation. For example, drug addiction, lack of sex desire, eating disorders, such as anorexia or bulimia and dyssomnias. eCBs also participate in the regulation of core temperature and pain perception. In this context, it is important to recognize the utility of cannabinoid receptor 1 (CB1R) agonists, natural as D 9 -tetrahydrocannabinol (THC) or synthetic as Nabilone as useful drugs to alleviate this kind of patients' suffering. Therefore, we have developed a new drug, (R,Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-yl phenylacetate (PhAR-DBH-Me), that appears to bind and activate the CB1R. This diazabicyclic amide was synthesized from phenylacetylricinoleic acid and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane. To test its cannabinergic properties we evaluated its effects on core temperature, pain perception, and the sleepwaking cycle of rats. Results indicate that 20 and 40 mg/kg of PhAR-DBH-Me readily reduced core temperature and increased pain perception threshold. In addition, 20 mg/kg increased REM sleep in otherwise normal rats. All these effects were prevented or attenuated by AM251, a CB1R antagonist. Place preference conditioning studies indicated that this molecule does not produce rewarding effects. These results strongly support that PhAR-DBH-Me possesses cannabinoid activity without the reinforcement effects.
Biotransformations of morphine alkaloids by fungi: N-demethylations, oxidations, and reductions
Collection of …, 2009
Morphine alkaloids and some of its derivatives (morphine, codeine, thebaine, oripavine, hydrocodone, and oxycodone) were subjected to fermentations with six fungal strains. The alkaloids were transformed to a variety of products via biological oxidations, reductions, and oxidative demethylations. The strain Cunninghamella echinulata proved to be the most effective for demethylations of all of the above compounds, except for morphine. The time profile of the conversion of 3-[ 14 CH 3 ]thebaine to 3-[ 14 CH 3 ]northebaine by C. echinulata cultures was also determined.
MedChemComm, 2012
The biosynthesis of fungal bicyclo[2.2.2]diazaoctane indole alkaloids with a wide spectrum of biological activities have attracted increasing interest. Their intriguing mode of assembly has long been proposed to feature a non-ribosomal peptide synthetase, a presumed intramolecular Diels-Alderase, a variant number of prenyltransferases, and a series of oxidases responsible for the diverse tailoring modifications of their cyclodipeptide-based structural core. Until recently, the details of these biosynthetic pathways have remained largely unknown due to lack of information on the fungal derived biosynthetic gene clusters. Herein, we report a comparative analysis of four natural product metabolic systems of a select group of bicyclo[2.2.2]diazaoctane indole alkaloids including (+)/(−)-notoamide, paraherquamide and malbrancheamide, in which we propose an enzyme for each step in the biosynthetic pathway based on deep annotation and on-going biochemical studies.
Fungal biotransformation of morphine alkaloids
2009
The purpose of the study was to determine the ability of certain fungi to biotransform morphine alkaloids into medicinally relevant intermediates. Fungal strains screened for their ability to affect biotransformation of morphine alkaloids include Cunninghamella echinulata, Helicostylum pirijorme, Pycnoporus sanguinea, Pycnoporus cinnabarina, Curvularia lunata and Sporotrichum sulfurescens. The research demonstrated that Cunninghamella echinulata N-demethylated thebaine, hydrocodone, codeine, oripavine and oxycodone into corresponding nor-compounds in varying yields. The study further focused on the characterization of the enzyme responsible for the biotransformation of thebaine into northebaine by Cunninghamella echinulata. The study clearly showed that incubation of the fungal culture with thebaine over a period of 48 hours was required to activate the biotransformation process. The biotransformation studies with [14C] labeled thebaine showed that Ndemethylation by Cunningham ella echinulata does not involve O-demethylation followed by methyl group transfer as suggested in previous studies. iii List of Tables vii List of Figures viii List of Abbreviations IX 3.1.1. N-demethylation of morphine alkaloids 29 3.1.2. C14-hydroxylation of morphine alkaloids v 3.2. Characterization of the enzyme involved in demethylation of morphine alkaloids from Cunningham ella echinulata 3.2.1. Biotransformation of thebaine into northebaine by cultures of Cunningham ella echinulata 3.2.2. Pretreatment of cultures of Cunninghamella echinulata with a low dose of thebaine induces the components required for biotransformation of thebaine into northebaine 3.3. Identification of enzymes involved in the biotransformation of thebaine into northebaine in Cunninghamella echinulata cultures 3.3.1. Characteristics of enzymes involved in demethylation reactions 42 3.3.2. Putative mechanisms for N-demethylation of. morphine alkaloids 42 3.3.3. In vitro enzyme assay development for conversion of thebaine into northebaine 3.3.4. Cell free extracts assayed under different conditions do not convert thebaine into northebaine 3.3.5. Biotransformation of 3e4CH3J thebaine into 3[14CH3J northebaine by cultures of Cunninghamella echinulata 3.3.6. Cell free extracts assayed under different conditions do not convert 3[14CH3J thebaine 43
Total synthesis of morphine and related alkaloids
Synthesis of morphine-like alkaloids in chemistry describes the total synthesis of the natural morphinan class of alkaloids that includescodeine, morphine, oripavine, and thebaine and the closely related semisynthetic analogs buprenorphine, hydrocodone, isocodeine,naltrexone, naloxone, na lbuphine, and oxycodone. [1] The structure of morphine is not particularly complex, however the electrostatic polarization of adjacent bonded atoms does not alternate uniformly throughout the structure. This "dissonant connectivity" makes bond formation more difficult and therefore significantly complicates any synthetic strategy that is applied to this family of molecules. The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952 remains a widely used example of total synthesis. This synthesis took a total of 31 steps and proceeded in 0.06% over all yield. The dihydrocodeinone synthesis of Rice is one of the most efficient and proceeds in 30% overall yield in 14 steps. Several other syntheses were reported, notably by the research groups of Evans, Fuchs,
Syntheses of Morphine and Codeine (1992-2002): Templates for Exploration of Synthetic Tools
ChemInform, 2006
Morphine (1) and its O-methylated analogue codeine (2), analgesic alkaloids of the opium poppy (Papaver Somniferium), have been targets of organic chemists engaged in synthetic activities for at least half a century. The "first" (Gates) and "most efficient" (Rice) syntheses of morphine (1) and codeine (2) are well known and have been reviewed and analyzed extensively numerous times. However, syntheses of the same two alkaloids that have been reported since 1992 and which have been used as devices to advance the art of organic synthesis are not as widely recognized and they have not been as thoroughly reviewed. Here they are analyzed in the spirit of the use of these two compounds as templates. Further, since both racemic and enantiospecific syntheses are important and since all eight (8) approaches (since 1992) are sufficiently different so as to warrant more tha n superficial examination, they are all considered.