The Experts below are selected from a list of 2028 Experts worldwide ranked by ideXlab platform
John L. Neumeyer - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacological evaluation of 6 7 indolo thiazolo Morphinans further sar of levorphanol
Journal of Medicinal Chemistry, 2007Co-Authors: Ao Zhang, Chunyong Ding, Brian I Knapp, Jean M Bidlack, Fuying Li, John L. NeumeyerAbstract:To further extend the structure−activity relationships of levorphanol, two series of novel Morphinans were prepared by incorporation of an indole or aminothiazole fragment to the hexyl ring (ring C) in levorphanol. Such Morphinans differed from previously reported ligands in that such indole- or aminothiazole-containing Morphinans displayed enhanced binding affinity to the δ opioid receptor, while the affinity to κ and μ receptors was slightly reduced.
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Synthesis and pharmacological evaluation of 6,7-indolo/thiazolo-Morphinans--further SAR of levorphanol.
Journal of Medicinal Chemistry, 2007Co-Authors: Ao Zhang, Chunyong Ding, Brian I Knapp, Jean M Bidlack, Fuying Li, John L. NeumeyerAbstract:To further extend the structure−activity relationships of levorphanol, two series of novel Morphinans were prepared by incorporation of an indole or aminothiazole fragment to the hexyl ring (ring C) in levorphanol. Such Morphinans differed from previously reported ligands in that such indole- or aminothiazole-containing Morphinans displayed enhanced binding affinity to the δ opioid receptor, while the affinity to κ and μ receptors was slightly reduced.
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characterization of a novel bivalent Morphinan possessing κ agonist and μ agonist antagonist properties
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Jennifer L. Mathews, John L. Neumeyer, Ao Zhang, Wennan Xiong, Xuemei Peng, Stevens S Negus, Jean M BidlackAbstract:Previous research has shown that compounds with mixed κ and μ activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent Morphinan that was shown to be a κ opioid receptor agonist and a μ opioid receptor agonist/antagonist. MCL-145 [bis( N -cyclobutylmethylMorphinan) fumarate] is related to the Morphinan cyclorphan and its N -cyclobutylmethyl derivative MCL-101 [3-hydroxy- N -cyclobutylmethyl Morphinan S -(+)-mandelate]. MCL-145 consists of two Morphinans connected by a spacer at the 3-hydroxy position. This compound had K i values of 0.078 and 0.20 nM for the κ and μ opioid receptors, respectively, using radioligand binding assays as shown by [Neumeyer et al. in 2003][1]. In the guanosine 5′- O -(3-[35 S]thiotriphosphate) binding assay, MCL-145 produced an E max value of 80% for the κ opioid receptor and 42% for the μ opioid receptor. The EC50 values obtained for this compound were 4.3 and 3.1 nM for the κ and μ opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the μ-selective antagonist β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. MCL-145 also acted as a μ antagonist, as measured by the inhibition of morphine-induced antinociception. [1]: #ref-20
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Characterization of a Novel Bivalent Morphinan Possessing κ Agonist and μ Agonist/Antagonist Properties
The Journal of pharmacology and experimental therapeutics, 2005Co-Authors: Jennifer L. Mathews, John L. Neumeyer, Ao Zhang, Wennan Xiong, S. Stevens Negus, Xuemei Peng, Jean M BidlackAbstract:Previous research has shown that compounds with mixed κ and μ activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent Morphinan that was shown to be a κ opioid receptor agonist and a μ opioid receptor agonist/antagonist. MCL-145 [bis( N -cyclobutylmethylMorphinan) fumarate] is related to the Morphinan cyclorphan and its N -cyclobutylmethyl derivative MCL-101 [3-hydroxy- N -cyclobutylmethyl Morphinan S -(+)-mandelate]. MCL-145 consists of two Morphinans connected by a spacer at the 3-hydroxy position. This compound had K i values of 0.078 and 0.20 nM for the κ and μ opioid receptors, respectively, using radioligand binding assays as shown by [Neumeyer et al. in 2003][1]. In the guanosine 5′- O -(3-[35 S]thiotriphosphate) binding assay, MCL-145 produced an E max value of 80% for the κ opioid receptor and 42% for the μ opioid receptor. The EC50 values obtained for this compound were 4.3 and 3.1 nM for the κ and μ opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the μ-selective antagonist β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. MCL-145 also acted as a μ antagonist, as measured by the inhibition of morphine-induced antinociception. [1]: #ref-20
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Design and Synthesis of Novel Dimeric Morphinan Ligands for κ and μ Opioid Receptors
Journal of medicinal chemistry, 2003Co-Authors: John L. Neumeyer, Brian I Knapp, Ao Zhang, Wennan Xiong, James E. Hilbert, S. Stevens Negus, Nancy K. Mello, Jean M BidlackAbstract:A novel series of Morphinans were synthesized, and their binding affinity at and functional selectivity for micro, delta, and kappa opioid receptors were evaluated. These dimeric ligands can be viewed as dimeric Morphinans, which were formed by coupling two identical Morphinan pharmacophores (cyclorphan (1) or MCL 101 (2)) with varying connecting spacers. Ligands 6 and 7 with alkyl spacers on the nitrogen position and ligands 8 and 9 in which the two Morphinan pharmacophores were coupled by ether moieties at the 3-hydroxyl positions showed significant decrease in affinity at all three opioid receptors. An improvement in the affinity was achieved by introducing an ester moiety as the spacer in the dimeric Morphinans. It was observed that the affinity of these ligands was sensitive to the character and length of the spacer. Compound 13 (MCL-139) with a 4-carbon ester spacer, compound 17 (MCL-144) containing a 10-carbon spacer, and compound 19 (MCL-145) with the conformationally constrained fumaryl spacer were the most potent ligands in this series, displaying excellent affinities at micro and kappa receptors (K(i) = 0.09-0.2 nM at micro and K(i) = 0.078-0.049 nM at kappa), which were comparable to the parent compound 2. Ligand 12, a compound containing only one Morphinan pharmacophore and a long-chain ester group, had affinity at both micro and kappa receptors almost identical to that of the parent ligand 2. In the [(35)S]GTPgammaS binding assay, ligands 13, 17, and 19 and their parent Morphinans 1 and 2 stimulated [(35)S]GTPgammaS binding mediated by the micro and kappa receptors. Compounds 13 and 17 were full kappa agonists and partial micro agonists, while compound 19 was a partial agonist at both micro and kappa receptors. These novel ligands, as well as their interesting pharmacological properties, will serve as the basis for our continuing investigation of the dimeric ligands as potential probes for the pharmacotherapy of cocaine abuse and may also open new avenues for the characterization of opioid receptors.
Sándor Hosztafi - One of the best experts on this subject based on the ideXlab platform.
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Determination of 6-oxo-Morphinans, as the oximes, by difference circular dichroism spectroscopy.
Analytical and bioanalytical chemistry, 2002Co-Authors: A. Szentesi, Sándor Hosztafi, András Gergely, P. Horváth, Gy. SzászAbstract:A negative Cotton effect is observed in the circular dichroism (CD) spectra of 6-oxo-Morphinans in the wavelength range of n–π* electron transitions. 6-oxo-Morphinans can be transformed into oxime derivatives with hydroxylamine and after oxime formation the CD spectra are significantly different. Oxime formation was monitored by CD and by HPLC. It was established that under the experimental conditions used oxime formation was complete within 90 min. The method suggested for the determination of 6-oxo-Morphinans is based on the considerable differences between the ellipticities before and after the oxime formation. The ellipticity difference varies linearly with concentration in the range 2×10–5–5×10–4 mol L–1 for the three 6-oxo-Morphinans examined (oxycodone, hydrocodone, and 14-hydroxycodeinone). For hydrocodone the dependence is also linear in a lower concentration range (5×10–6–10–4 mol L–1). The new difference CD spectroscopic method can be applied to the selective determination of 6-oxo-Morphinans in bulk and dosage forms.
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reaction of Morphinan 6 8 dienes with azadienophiles
Tetrahedron, 1996Co-Authors: János Marton, Zoltán Szabó, Sándor Hosztafi, Istvan Csorvassy, Csaba Simon, Sándor MakleitAbstract:Reaction of various Morphinan dienes, i.e. thebaine (la), N-demethyl-N- formylthebaine (lb), 6-demethoxythebaine (le), 13-dihydrothebaine (2a), 4-acetoxy-~-dihydrothebaine (2b), 7-chloro-6-demethoxythebaine (3a) and 7-bromo-6-demethoxythebaine (3b) with 4-phenyl-4H- 1,2,4-triazoline-3,5-dione (PTAD) gave rise to new Diels-Alder (DA) adducts. DA-reaction of la, lb and 1¢ with PTAD led to the products of the 13-face attack of the dienophile at the diene unit. The W coupling (4J5~,18) in the IH-NMR spectra was indicative of these structures, o~-Face addition took place in the case of Morphinan dienes with opened ring E, and a by-product was formed due to the SE reaction of PTAD with the adducts. The structure of these derivatives was confirmed by means of NMR spectroscopic methods. The retro Diels-Alder (rDA) reaction of the adducts 4a and 4b readily took place in polar-aprotic solvents in the presence of bases with low nucleophilic character.
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Reaction of Morphinan-6,8-dienes with Azadienophiles +**
Tetrahedron, 1996Co-Authors: János Marton, Zoltán Szabó, Sándor Hosztafi, Istvan Csorvassy, Csaba Simon, Sándor MakleitAbstract:Reaction of various Morphinan dienes, i.e. thebaine (la), N-demethyl-N- formylthebaine (lb), 6-demethoxythebaine (le), 13-dihydrothebaine (2a), 4-acetoxy-~-dihydrothebaine (2b), 7-chloro-6-demethoxythebaine (3a) and 7-bromo-6-demethoxythebaine (3b) with 4-phenyl-4H- 1,2,4-triazoline-3,5-dione (PTAD) gave rise to new Diels-Alder (DA) adducts. DA-reaction of la, lb and 1¢ with PTAD led to the products of the 13-face attack of the dienophile at the diene unit. The W coupling (4J5~,18) in the IH-NMR spectra was indicative of these structures, o~-Face addition took place in the case of Morphinan dienes with opened ring E, and a by-product was formed due to the SE reaction of PTAD with the adducts. The structure of these derivatives was confirmed by means of NMR spectroscopic methods. The retro Diels-Alder (rDA) reaction of the adducts 4a and 4b readily took place in polar-aprotic solvents in the presence of bases with low nucleophilic character.
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synthesis and stereostructure of some spiro Morphinan 6 2 3 h 1 3 4 oxa thia diazolines
Liebigs Annalen, 1995Co-Authors: László Somogyi, Zoltán Szabó, Sándor HosztafiAbstract:Treatment of dihydrocodeinone (thio)semicarbazones 1a–d with Ac2O/ZnCl2 afforded (6S)-spiro[Morphinan-6,2′(3′H)-[1,3,4]oxadiazolines] (2a, b) and (6R)-spiro[Morphinan-6,2′-(3′H)-[1,3,4]thiadiazolines] (3a, b), respectively. The structure of the products including the configuration of the spiro carbons was determined by 1H- and 13C-NMR measurements.
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Synthesis and stereostructure of some spiro[Morphinan‐6,2′(3′H)‐[1,3,4]oxa(thia)diazolines]
Liebigs Annalen, 1995Co-Authors: László Somogyi, Zoltán Szabó, Sándor HosztafiAbstract:Treatment of dihydrocodeinone (thio)semicarbazones 1a–d with Ac2O/ZnCl2 afforded (6S)-spiro[Morphinan-6,2′(3′H)-[1,3,4]oxadiazolines] (2a, b) and (6R)-spiro[Morphinan-6,2′-(3′H)-[1,3,4]thiadiazolines] (3a, b), respectively. The structure of the products including the configuration of the spiro carbons was determined by 1H- and 13C-NMR measurements.
Anthony John Fist - One of the best experts on this subject based on the ideXlab platform.
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Increasing Morphinan alkaloid production by over‐expressing codeinone reductase in transgenic Papaver somniferum
Plant biotechnology journal, 2007Co-Authors: Philip J. Larkin, Toni M. Kutchan, James A. C. Miller, Robert S. Allen, Julie A. Chitty, Wayne Gerlach, Susanne Frick, Anthony John FistAbstract:Summary Only plants of the Papaver genus (poppies) are able to synthesize Morphinan alkaloids, and cultivation of P. somniferum, opium poppy, remains critical for the production and supply of morphine, codeine and various semi-synthetic analgesics. Opium poppy was transformed with constitutively expressed cDNA of codeinone reductase (PsCor1.1), the penultimate step in morphine synthesis. Most transgenic lines showed significant increases in capsule alkaloid content in replicated glasshouse and field trials over 4 years. The Morphinan alkaloid contents on a dry weight basis were between 15% and 30% greater than those in control high-yielding genotypes and control non-transgenic segregants. Transgenic leaves had approximately 10-fold greater levels of Cor transcript compared with non-transgenic controls. Two cycles of crossing of the best transgenic line into an elite high-morphine genotype resulted in significant increases in morphine and total alkaloids relative to the elite recurrent parent. No significant changes in alkaloid profiles or quantities were observed in leaf, roots, pollen and seed.
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increasing Morphinan alkaloid production by over expressing codeinone reductase in transgenic papaver somniferum
Plant Biotechnology Journal, 2007Co-Authors: Philip J. Larkin, Toni M. Kutchan, James A. C. Miller, Robert S. Allen, Julie A. Chitty, Wayne Gerlach, Susanne Frick, Anthony John FistAbstract:Summary Only plants of the Papaver genus (poppies) are able to synthesize Morphinan alkaloids, and cultivation of P. somniferum, opium poppy, remains critical for the production and supply of morphine, codeine and various semi-synthetic analgesics. Opium poppy was transformed with constitutively expressed cDNA of codeinone reductase (PsCor1.1), the penultimate step in morphine synthesis. Most transgenic lines showed significant increases in capsule alkaloid content in replicated glasshouse and field trials over 4 years. The Morphinan alkaloid contents on a dry weight basis were between 15% and 30% greater than those in control high-yielding genotypes and control non-transgenic segregants. Transgenic leaves had approximately 10-fold greater levels of Cor transcript compared with non-transgenic controls. Two cycles of crossing of the best transgenic line into an elite high-morphine genotype resulted in significant increases in morphine and total alkaloids relative to the elite recurrent parent. No significant changes in alkaloid profiles or quantities were observed in leaf, roots, pollen and seed.
Jean M Bidlack - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacological evaluation of 6 7 indolo thiazolo Morphinans further sar of levorphanol
Journal of Medicinal Chemistry, 2007Co-Authors: Ao Zhang, Chunyong Ding, Brian I Knapp, Jean M Bidlack, Fuying Li, John L. NeumeyerAbstract:To further extend the structure−activity relationships of levorphanol, two series of novel Morphinans were prepared by incorporation of an indole or aminothiazole fragment to the hexyl ring (ring C) in levorphanol. Such Morphinans differed from previously reported ligands in that such indole- or aminothiazole-containing Morphinans displayed enhanced binding affinity to the δ opioid receptor, while the affinity to κ and μ receptors was slightly reduced.
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Synthesis and pharmacological evaluation of 6,7-indolo/thiazolo-Morphinans--further SAR of levorphanol.
Journal of Medicinal Chemistry, 2007Co-Authors: Ao Zhang, Chunyong Ding, Brian I Knapp, Jean M Bidlack, Fuying Li, John L. NeumeyerAbstract:To further extend the structure−activity relationships of levorphanol, two series of novel Morphinans were prepared by incorporation of an indole or aminothiazole fragment to the hexyl ring (ring C) in levorphanol. Such Morphinans differed from previously reported ligands in that such indole- or aminothiazole-containing Morphinans displayed enhanced binding affinity to the δ opioid receptor, while the affinity to κ and μ receptors was slightly reduced.
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characterization of a novel bivalent Morphinan possessing κ agonist and μ agonist antagonist properties
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Jennifer L. Mathews, John L. Neumeyer, Ao Zhang, Wennan Xiong, Xuemei Peng, Stevens S Negus, Jean M BidlackAbstract:Previous research has shown that compounds with mixed κ and μ activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent Morphinan that was shown to be a κ opioid receptor agonist and a μ opioid receptor agonist/antagonist. MCL-145 [bis( N -cyclobutylmethylMorphinan) fumarate] is related to the Morphinan cyclorphan and its N -cyclobutylmethyl derivative MCL-101 [3-hydroxy- N -cyclobutylmethyl Morphinan S -(+)-mandelate]. MCL-145 consists of two Morphinans connected by a spacer at the 3-hydroxy position. This compound had K i values of 0.078 and 0.20 nM for the κ and μ opioid receptors, respectively, using radioligand binding assays as shown by [Neumeyer et al. in 2003][1]. In the guanosine 5′- O -(3-[35 S]thiotriphosphate) binding assay, MCL-145 produced an E max value of 80% for the κ opioid receptor and 42% for the μ opioid receptor. The EC50 values obtained for this compound were 4.3 and 3.1 nM for the κ and μ opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the μ-selective antagonist β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. MCL-145 also acted as a μ antagonist, as measured by the inhibition of morphine-induced antinociception. [1]: #ref-20
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Characterization of a Novel Bivalent Morphinan Possessing κ Agonist and μ Agonist/Antagonist Properties
The Journal of pharmacology and experimental therapeutics, 2005Co-Authors: Jennifer L. Mathews, John L. Neumeyer, Ao Zhang, Wennan Xiong, S. Stevens Negus, Xuemei Peng, Jean M BidlackAbstract:Previous research has shown that compounds with mixed κ and μ activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent Morphinan that was shown to be a κ opioid receptor agonist and a μ opioid receptor agonist/antagonist. MCL-145 [bis( N -cyclobutylmethylMorphinan) fumarate] is related to the Morphinan cyclorphan and its N -cyclobutylmethyl derivative MCL-101 [3-hydroxy- N -cyclobutylmethyl Morphinan S -(+)-mandelate]. MCL-145 consists of two Morphinans connected by a spacer at the 3-hydroxy position. This compound had K i values of 0.078 and 0.20 nM for the κ and μ opioid receptors, respectively, using radioligand binding assays as shown by [Neumeyer et al. in 2003][1]. In the guanosine 5′- O -(3-[35 S]thiotriphosphate) binding assay, MCL-145 produced an E max value of 80% for the κ opioid receptor and 42% for the μ opioid receptor. The EC50 values obtained for this compound were 4.3 and 3.1 nM for the κ and μ opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the μ-selective antagonist β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. MCL-145 also acted as a μ antagonist, as measured by the inhibition of morphine-induced antinociception. [1]: #ref-20
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Design and Synthesis of Novel Dimeric Morphinan Ligands for κ and μ Opioid Receptors
Journal of medicinal chemistry, 2003Co-Authors: John L. Neumeyer, Brian I Knapp, Ao Zhang, Wennan Xiong, James E. Hilbert, S. Stevens Negus, Nancy K. Mello, Jean M BidlackAbstract:A novel series of Morphinans were synthesized, and their binding affinity at and functional selectivity for micro, delta, and kappa opioid receptors were evaluated. These dimeric ligands can be viewed as dimeric Morphinans, which were formed by coupling two identical Morphinan pharmacophores (cyclorphan (1) or MCL 101 (2)) with varying connecting spacers. Ligands 6 and 7 with alkyl spacers on the nitrogen position and ligands 8 and 9 in which the two Morphinan pharmacophores were coupled by ether moieties at the 3-hydroxyl positions showed significant decrease in affinity at all three opioid receptors. An improvement in the affinity was achieved by introducing an ester moiety as the spacer in the dimeric Morphinans. It was observed that the affinity of these ligands was sensitive to the character and length of the spacer. Compound 13 (MCL-139) with a 4-carbon ester spacer, compound 17 (MCL-144) containing a 10-carbon spacer, and compound 19 (MCL-145) with the conformationally constrained fumaryl spacer were the most potent ligands in this series, displaying excellent affinities at micro and kappa receptors (K(i) = 0.09-0.2 nM at micro and K(i) = 0.078-0.049 nM at kappa), which were comparable to the parent compound 2. Ligand 12, a compound containing only one Morphinan pharmacophore and a long-chain ester group, had affinity at both micro and kappa receptors almost identical to that of the parent ligand 2. In the [(35)S]GTPgammaS binding assay, ligands 13, 17, and 19 and their parent Morphinans 1 and 2 stimulated [(35)S]GTPgammaS binding mediated by the micro and kappa receptors. Compounds 13 and 17 were full kappa agonists and partial micro agonists, while compound 19 was a partial agonist at both micro and kappa receptors. These novel ligands, as well as their interesting pharmacological properties, will serve as the basis for our continuing investigation of the dimeric ligands as potential probes for the pharmacotherapy of cocaine abuse and may also open new avenues for the characterization of opioid receptors.
Vincent J. J. Martin - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Morphinan Alkaloids in Saccharomyces cerevisiae.
PloS one, 2015Co-Authors: Elena Fossati, Lauren Narcross, Andrew Ekins, Jean-pierre Falgueyret, Vincent J. J. MartinAbstract:Morphinan alkaloids are the most powerful narcotic analgesics currently used to treat moderate to severe and chronic pain. The feasibility of Morphinan synthesis in recombinant Saccharomyces cerevisiae starting from the precursor (R,S)-norlaudanosoline was investigated. Chiral analysis of the reticuline produced by the expression of opium poppy methyltransferases showed strict enantioselectivity for (S)-reticuline starting from (R,S)-norlaudanosoline. In addition, the P. somniferum enzymes salutaridine synthase (PsSAS), salutaridine reductase (PsSAR) and salutaridinol acetyltransferase (PsSAT) were functionally co-expressed in S. cerevisiae and optimization of the pH conditions allowed for productive spontaneous rearrangement of salutaridinol-7-O-acetate and synthesis of thebaine from (R)-reticuline. Finally, we reconstituted a 7-gene pathway for the production of codeine and morphine from (R)-reticuline. Yeast cell feeding assays using (R)-reticuline, salutaridine or codeine as substrates showed that all enzymes were functionally co-expressed in yeast and that activity of salutaridine reductase and codeine-O-demethylase likely limit flux to morphine synthesis. The results of this study describe a significant advance for the synthesis of Morphinans in S. cerevisiae and pave the way for their complete synthesis in recombinant microbes.
