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Wayne W. Harding - One of the best experts on this subject based on the ideXlab platform.
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identification of c10 nitrogen containing Aporphines with dopamine d1 versus d5 receptor selectivity
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Anupam Karki, Wayne W. Harding, Reecan Juarez, Hari K Namballa, Ian AlbertsAbstract:New Aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT1A and 5-HT2A receptors and at human dopamine D1, D2 and D5 receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic Aporphine core and series B which are 1,2,10-trisubstituted Aporphines. Remarkably, compounds from both series lacked affinity for the D5 receptor, thus attaining D1 versus D5 selectivity. Compound 20c was the most potent D1 ligand identified. Docking studies at D1 and D5 receptors indicate that the binding mode of 20c at the D1 receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D5 receptor, accounting for its D1 versus D5 selectivity. Considering the lack of affinity for the D5 receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of Aporphines as sub-type selective D1 receptor tools.
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Structure-activity profiling of alkaloid natural product pharmacophores against a Schistosoma serotonin receptor
Elsevier, 2018Co-Authors: Jonathan S. Marchant, Wayne W. Harding, John D. ChanAbstract:Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscular function to sexual maturation and egg laying. In the parasitic blood fluke Schistosoma mansoni, 5-HT targets several G-protein coupled receptors (GPCRs), one of which has been demonstrated to couple to cAMP and regulate parasite movement. This receptor, Sm.5HTRL, has been successfully co-expressed in mammalian cells alongside a luminescent cAMP-biosensor, enabling pharmacological profiling for candidate anti-schistosomal drugs. Here, we have utilized this assay to perform structure-activity investigations of 143 compounds containing previously identified alkaloid natural product pharmacophores (tryptamines, Aporphines and protoberberines) shown to regulate Sm.5HTRL. These experiments mapped regions of the tryptamine pharmacophore amenable and intolerant to substitution, highlighting differences relative to orthologous mammalian 5-HT receptors. Potent Sm.5HTRL antagonists were identified, and the efficacy of these compounds were evaluated against live adult parasites cultured ex vivo. Such structure-activity profiling, characterizing the effect of various modifications to these core ring systems on Sm.5HTRL responses, provides greater understanding of pharmacophores selective for this target to aid future drug development efforts. Keywords: Tryptamine, Aporphine, Protoberberine, Benzylisoquinoline, Schistosomiasis, G protein coupled recepto
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Aporphine alkaloids as ligands for serotonin receptors
Medicinal Chemistry, 2016Co-Authors: Nirav Kapadia, Wayne W. HardingAbstract:The Aporphine alkaloids are known to have affinities as the dopaminergic, adrenergic and serotonergic receptor system. Hence the Aporphine template can be considered as a privileged scaffold for the design of selective monopotent as well as multi-potent Central Nervous System (CNS) ligands. This review attempts to summarize the recent Structure Activity Relationship (SAR) studies of Aporphine alkaloids specifically at the serotonin receptor system. Based on the obtained SAR information it can be concluded that Aporphines have great potential to be developed as potent serotonergic ligands.
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evaluation of structural effects on 5 ht 2a receptor antagonism by Aporphines identification of a new Aporphine with 5 ht 2a antagonist activity
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Shashikanth Ponnala, Wayne W. Harding, Nirav Kapadia, Junior Gonzales, Hernan A NavarroAbstract:A set of Aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT2A and α1A adrenergic receptors. With regards to 5-HT2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT2A antagonism. Compound 12b was the most potent 5-HT2A Aporphine antagonist identified in this study and has similar potency to previously identified Aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to α1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to α1A antagonism.
Alma Rosa González-esquinca - One of the best experts on this subject based on the ideXlab platform.
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Aporphine alkaloid contents increase with moderate nitrogen supply in Annona diversifolia Saff. (Annonaceae) seedlings during diurnal periods
Natural product research, 2016Co-Authors: José Agustín Orozco-castillo, Rocío Cruz-ortega, Mariano Martínez-vázquez, Alma Rosa González-esquincaAbstract:AbstractAporphine alkaloids are secondary metabolites that are obtained in low levels from species of the Annonaceae family. Nitrogen addition may increase the alkaloid content in plants. However, previous studies published did not consider that nitrogen could change the alkaloid content throughout the day. We conducted this short-term study to determine the effects of nitrogen applied throughout the diurnal period on the Aporphine alkaloids via measurements conducted on the roots, stems and leaves of Annona diversifolia seedlings. The 60-day-old seedlings were cultured with the addition of three levels of nitrogen (0, 30 and 60 mM), and alkaloid extracts were analysed using high-performance liquid chromatography. The highest total alkaloid content was measured in the treatment with moderate nitrogen supply. Further, the levels of Aporphine alkaloids changed significantly in the first few hours of the diurnal period. We conclude that Aporphine alkaloid content increased with moderate nitrogen supply and e...
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Aporphine alkaloid contents increase with moderate nitrogen supply in Annona diversifolia Saff. (Annonaceae) seedlings during diurnal periods
2016Co-Authors: José Agustín Orozco-castillo, Rocío Cruz-ortega, Mariano Martínez-vázquez, Alma Rosa González-esquincaAbstract:Aporphine alkaloids are secondary metabolites that are obtained in low levels from species of the Annonaceae family. Nitrogen addition may increase the alkaloid content in plants. However, previous studies published did not consider that nitrogen could change the alkaloid content throughout the day. We conducted this short-term study to determine the effects of nitrogen applied throughout the diurnal period on the Aporphine alkaloids via measurements conducted on the roots, stems and leaves of Annona diversifolia seedlings. The 60-day-old seedlings were cultured with the addition of three levels of nitrogen (0, 30 and 60 mM), and alkaloid extracts were analysed using high-performance liquid chromatography. The highest total alkaloid content was measured in the treatment with moderate nitrogen supply. Further, the levels of Aporphine alkaloids changed significantly in the first few hours of the diurnal period. We conclude that Aporphine alkaloid content increased with moderate nitrogen supply and exhibited diurnal variation.
Cristiano Raminelli - One of the best experts on this subject based on the ideXlab platform.
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a convenient formation of Aporphine core via benzyne chemistry conformational analysis and synthesis of r Aporphine
Tetrahedron Letters, 2015Co-Authors: Givago P Perecim, Alessandro Rodrigues, Cristiano RaminelliAbstract:Abstract Total synthesis of ( R )-Aporphine has been accomplished by an approach that employs in the key step a sequence of transformations involving a [4+2] cycloaddition reaction followed by a hydrogen migration, leading to Aporphine core in good yield, which was subjected to a 1D gradient NOE experiment, conformational analysis, and simple transformations, including a small scale resolution process, to afford enantiomerically enriched Aporphine alkaloid.
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total syntheses of Aporphine alkaloids via benzyne chemistry an approach to the formation of Aporphine cores
Journal of Organic Chemistry, 2015Co-Authors: Allan F C Rossini, Gleison A. Casagrande, Ana Carolina A. Muraca, Cristiano RaminelliAbstract:Total syntheses of lysicamine, (±)-nuciferine, (±)-nornuciferine, (±)-zanthoxyphylline iodide, (±)-O-methylisothebaine, and (±)-trimethoxynorAporphine were accomplished by an approach that involves the formation of Aporphine cores through reactions between an isoquinoline derivative and silylaryl triflates promoted by CsF. Unprecedented formations of Aporphine cores proceeded in good yields presumably through [4 + 2] cycloaddition reactions followed by hydrogen migrations.
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Total Syntheses of Aporphine Alkaloids via Benzyne Chemistry: An Approach to the Formation of Aporphine Cores
2015Co-Authors: Allan F. C. Rossini, Ana Carolina A. Muraca, Gleison A. Casagrande, Cristiano RaminelliAbstract:Total syntheses of lysicamine, (±)-nuciferine, (±)-nornuciferine, (±)-zanthoxyphylline iodide, (±)-O-methylisothebaine, and (±)-trimethoxynorAporphine were accomplished by an approach that involves the formation of Aporphine cores through reactions between an isoquinoline derivative and silylaryl triflates promoted by CsF. Unprecedented formations of Aporphine cores proceeded in good yields presumably through [4 + 2] cycloaddition reactions followed by hydrogen migrations
José Agustín Orozco-castillo - One of the best experts on this subject based on the ideXlab platform.
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Aporphine alkaloid contents increase with moderate nitrogen supply in Annona diversifolia Saff. (Annonaceae) seedlings during diurnal periods
Natural product research, 2016Co-Authors: José Agustín Orozco-castillo, Rocío Cruz-ortega, Mariano Martínez-vázquez, Alma Rosa González-esquincaAbstract:AbstractAporphine alkaloids are secondary metabolites that are obtained in low levels from species of the Annonaceae family. Nitrogen addition may increase the alkaloid content in plants. However, previous studies published did not consider that nitrogen could change the alkaloid content throughout the day. We conducted this short-term study to determine the effects of nitrogen applied throughout the diurnal period on the Aporphine alkaloids via measurements conducted on the roots, stems and leaves of Annona diversifolia seedlings. The 60-day-old seedlings were cultured with the addition of three levels of nitrogen (0, 30 and 60 mM), and alkaloid extracts were analysed using high-performance liquid chromatography. The highest total alkaloid content was measured in the treatment with moderate nitrogen supply. Further, the levels of Aporphine alkaloids changed significantly in the first few hours of the diurnal period. We conclude that Aporphine alkaloid content increased with moderate nitrogen supply and e...
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Aporphine alkaloid contents increase with moderate nitrogen supply in Annona diversifolia Saff. (Annonaceae) seedlings during diurnal periods
2016Co-Authors: José Agustín Orozco-castillo, Rocío Cruz-ortega, Mariano Martínez-vázquez, Alma Rosa González-esquincaAbstract:Aporphine alkaloids are secondary metabolites that are obtained in low levels from species of the Annonaceae family. Nitrogen addition may increase the alkaloid content in plants. However, previous studies published did not consider that nitrogen could change the alkaloid content throughout the day. We conducted this short-term study to determine the effects of nitrogen applied throughout the diurnal period on the Aporphine alkaloids via measurements conducted on the roots, stems and leaves of Annona diversifolia seedlings. The 60-day-old seedlings were cultured with the addition of three levels of nitrogen (0, 30 and 60 mM), and alkaloid extracts were analysed using high-performance liquid chromatography. The highest total alkaloid content was measured in the treatment with moderate nitrogen supply. Further, the levels of Aporphine alkaloids changed significantly in the first few hours of the diurnal period. We conclude that Aporphine alkaloid content increased with moderate nitrogen supply and exhibited diurnal variation.
Jianguo Zeng - One of the best experts on this subject based on the ideXlab platform.
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systematic identification of alkaloids in macleaya microcarpa fruits by liquid chromatography tandem mass spectrometry combined with the isoquinoline alkaloids biosynthetic pathway
Journal of Pharmaceutical and Biomedical Analysis, 2015Co-Authors: Zhixing Qing, Pi Cheng, Xiubin Liu, Yisong Liu, Jianguo ZengAbstract:Abstract Alkaloids in Macleaya microcarpa were characterized systematically by combining liquid chromatography tandem mass spectrometry (LC–MS/MS) with the biosynthetic pathway of isoquinoline alkaloids. The mass spectral fragmentation behaviors of 16 references belonging to eight types of alkaloids that exist in the biosynthetic pathway of isoquinoline were investigated in detail. The benzyltetrahydroisoquinoline and Aporphine alkaloids were distinguished by characteristic losses of the NHR 1 R 2 (R 1 and R 2 represent the substituent groups of the nitrogen atom) radical and the fragment ions below m / z 200. Tetrahydroprotoberberine, N -methyltetrahydroberberine and protopine alkaloids were differentiated by the retro-Diels–Alder (RDA) reaction, α-cleavage and the [M–H 2 O] + and [M–CH 4 ] + ions. Discrimination of protoberberine, benzophenanthridine and dihydrobenzophenanthridine-type alkaloids can be realized through the characteristic [fragment ion-2H] + , [M–H 2 O] + , [M–CH 4 ] + , [M+H–CH 3 CH 2 CH 2 OH] + and [M+H–CH 3 COCH 3 ] + ions. Forty-one alkaloids, including one benzyltetrahydroisoquinoline, one Aporphine, nine protopines, seven protoberberines, one tetrahydroprotoberberine, three N -methyltetrahydroprotoberberines, five benzophenanthridines and fourteen dihydrobenzophenanthridines, were separated and identified simultaneously. Thirty-three of these were reported for the first time in M. microcarpa . The benzyltetrahydroisoquinoline, Aporphine, tetrahydroprotoberberine and N -methyltetrahydroprotoberberine-type alkaloids have not been reported previously in M. microcarpa . This method can be applied to the analysis of herbal medicines that possess the biosynthetic pathway of isoquinoline alkaloids.