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Hugo R. Arias - One of the best experts on this subject based on the ideXlab platform.
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Coronaridine congeners potentiate GABAA receptors and induce sedative activity in mice in a benzodiazepine-insensitive manner.
Progress in neuro-psychopharmacology & biological psychiatry, 2020Co-Authors: Hugo R. Arias, Jean Luc Do Rego, Jean-claude Do Rego, Zhenglan Chen, Youssef Anouar, Petra Scholze, Eric B. Gonzales, Ren-qi Huang, Abdeslam ChagraouiAbstract:Abstract To determine whether (+)-catharanthine induces sedative- or anxiolytic/anxiogenic-like activity in male mice, proper animal paradigms were used. The results showed that (+)-catharanthine induces sedative-like activity in the 63–72 mg/Kg dose range in a flumazenil-insensitive manner, but neither this effect nor anxiolytic/anxiogenic-like activity was observed at lower doses. To determine the underlying molecular mechanism of the sedative-like activity, electrophysiological and radioligand binding experiments were performed with (+)-catharanthine and (±)-18-methoxyCoronaridine [(±)-18-MC] on GABAA (GABAARs) and glycine receptors (GlyRs). Coronaridine congeners both activated and potentiated a variety of human (h) GABAARs, except hρ1. (+)-Catharanthine-induced potentiation followed this receptor selectivity (EC50's in μM): hα1β2 (4.6 ± 0.8) > hα2β2γ2 (12.6 ± 3.8) ~ hα1β2γ2 (14.4 ± 4.6) indicating that both α1 and α2 are equally important, whereas γ2 is not necessary. (+)-Catharanthine was >2-fold more potent and efficient than (±)-18-MC at hα1β2γ2. (+)-Catharanthine also potentiated, whereas (±)-18-MC inhibited, hα1 GlyRs with very low potency. Additional [3H]-flunitrazepam competition binding experiments using rat cerebellum membranes clearly demonstrated that these ligands do not bind to the benzodiazepine site. This is supported by the observed activity at hα1β2 (lacking the BDZ site) and similar effects between α1- and α2-containing GABAARs. Our study shows, for the first time, that (+)-catharanthine induced sedative-like effects in mice, and Coronaridine congeners potentiated human α1β2γ2, α1β2, and hα2β2γ2, but not ρ1, GABAARs, both in a benzodiazepine-insensitive fashion, whereas only (+)-catharanthine slightly potentiated GlyRs.
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Coronaridine congeners modulate mitochondrial α3β4 nicotinic acetylcholine receptors with different potency and through distinct intra mitochondrial pathways
Neurochemistry International, 2018Co-Authors: Hugo R. Arias, Olena Lykhmus, Kateryna Uspenska, Maryna SkokAbstract:In contrast to plasma membrane-expressed nicotinic acetylcholine receptors (nAChRs), mitochondrial nAChRs function in an ion-independent manner by triggering intra-mitochondrial kinases that regulate the release of cytochrome c (Cyt c), an important step in cellular apoptosis. The aim of this study is to determine the structural requirements for mitochondrial α3β4* nAChR activation by measuring the modulatory effects of two noncompetitive antagonists of these receptors, (+)-catharanthine and (±)-18-methoxyCoronaridine [(±)-18-MC], on Cyt c release from wild-type and α7-/- mice mitochondria. The sandwich ELISA results indicated that α3β4* nAChRs are present in liver mitochondria in higher amounts compared to that in brain mitochondria and that these receptors are up-regulated in α7-/- mice. Correspondingly, (±)-18-MC decreased Cyt c release from liver mitochondria of wild-type mice and from brain and liver mitochondria of α7-/- mice. The effect in wild-type mice mitochondria was mediated mainly by the Src-dependent pathway, regulating the apoptogenic activity of reactive oxygen species, while in α7-/- mice mitochondria, (±)-18-MC strongly affected the calcium-calmodulin kinase II-dependent pathway. In contrast, (+)-catharanthine was much less potent than (±)-18-MC and triggered several signaling pathways, suggesting the involvement of multiple nAChR subtypes. These results show for the first time that noncompetitive antagonists can induce mitochondrial α3β4* nAChR signaling, giving a more comprehensive understanding on the function of intracellular nAChR subtypes.
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selectivity of Coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula
The International Journal of Biochemistry & Cell Biology, 2017Co-Authors: Hugo R. Arias, Dominik Feuerbach, Xiao Tao Jin, Rm DrenanAbstract:The inhibitory activity of Coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca2+ influx results clearly establish that Coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxyCoronaridine [(±)-18-MC]>(+)-catharanthine>(±)-18-methylaminoCoronaridine [(±)-18-MAC] ∼ (±)-18-hydroxyCoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine>(±)-18-MC>(±)-18-HC>(±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27±4μM) and (±)-18-MC (28±6μM) on MHb (VI) neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupropion with (-)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, Coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.
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Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites.
The international journal of biochemistry & cell biology, 2015Co-Authors: Hugo R. Arias, Katarzyna M. Targowska-duda, Dominik Feuerbach, Krzysztof JozwiakAbstract:Abstract To characterize the interaction of Coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca 2+ influx results established that Coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC 50 's in μM) sequence: (−)-ibogamine (0.62 ± 0.23) ∼ (+)-catharanthine (0.68 ± 0.10) > (−)-ibogaine (0.95 ± 0.10) > (±)-18-methoxyCoronaridine [(±)-18-MC] (1.47 ± 0.21) > (−)-voacangine (2.28 ± 0.33) > (±)-18-methylaminoCoronaridine (2.62 ± 0.57 μM) ∼ (±)-18-hydroxyCoronaridine (2.81 ± 0.54) > (−)-noribogaine (6.82 ± 0.78). A good linear correlation ( r 2 = 0.771) between the calculated IC 50 values and their polar surface area was found, suggesting that this is an important structural feature for its activity. The radioligand competition results indicate that (±)-18-MC and (−)-ibogaine partially inhibit [ 3 H]imipramine binding by an allosteric mechanism. Molecular docking, molecular dynamics, and in silico mutation results suggest that protonated (−)-18-MC binds to luminal [i.e., β4-Phe255 (phenylalanine/valine ring; position 13′), and α3-Leu250 and β4-Leu251 (leucine ring; position 9′)], non-luminal, and intersubunit sites. The pharmacophore model suggests that nitrogens from the ibogamine core as well as methylamino, hydroxyl, and methoxyl moieties at position 18 form hydrogen bonds. Collectively our data indicate that Coronaridine congeners inhibit hα3β4 AChRs by blocking the ion channel's lumen and probably by additional negative allosteric mechanisms by interacting with a series of non-luminal sites.
Krzysztof Jozwiak - One of the best experts on this subject based on the ideXlab platform.
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Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites.
The international journal of biochemistry & cell biology, 2015Co-Authors: Hugo R. Arias, Katarzyna M. Targowska-duda, Dominik Feuerbach, Krzysztof JozwiakAbstract:Abstract To characterize the interaction of Coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca 2+ influx results established that Coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC 50 's in μM) sequence: (−)-ibogamine (0.62 ± 0.23) ∼ (+)-catharanthine (0.68 ± 0.10) > (−)-ibogaine (0.95 ± 0.10) > (±)-18-methoxyCoronaridine [(±)-18-MC] (1.47 ± 0.21) > (−)-voacangine (2.28 ± 0.33) > (±)-18-methylaminoCoronaridine (2.62 ± 0.57 μM) ∼ (±)-18-hydroxyCoronaridine (2.81 ± 0.54) > (−)-noribogaine (6.82 ± 0.78). A good linear correlation ( r 2 = 0.771) between the calculated IC 50 values and their polar surface area was found, suggesting that this is an important structural feature for its activity. The radioligand competition results indicate that (±)-18-MC and (−)-ibogaine partially inhibit [ 3 H]imipramine binding by an allosteric mechanism. Molecular docking, molecular dynamics, and in silico mutation results suggest that protonated (−)-18-MC binds to luminal [i.e., β4-Phe255 (phenylalanine/valine ring; position 13′), and α3-Leu250 and β4-Leu251 (leucine ring; position 9′)], non-luminal, and intersubunit sites. The pharmacophore model suggests that nitrogens from the ibogamine core as well as methylamino, hydroxyl, and methoxyl moieties at position 18 form hydrogen bonds. Collectively our data indicate that Coronaridine congeners inhibit hα3β4 AChRs by blocking the ion channel's lumen and probably by additional negative allosteric mechanisms by interacting with a series of non-luminal sites.
Dominik Feuerbach - One of the best experts on this subject based on the ideXlab platform.
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selectivity of Coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula
The International Journal of Biochemistry & Cell Biology, 2017Co-Authors: Hugo R. Arias, Dominik Feuerbach, Xiao Tao Jin, Rm DrenanAbstract:The inhibitory activity of Coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca2+ influx results clearly establish that Coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxyCoronaridine [(±)-18-MC]>(+)-catharanthine>(±)-18-methylaminoCoronaridine [(±)-18-MAC] ∼ (±)-18-hydroxyCoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine>(±)-18-MC>(±)-18-HC>(±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27±4μM) and (±)-18-MC (28±6μM) on MHb (VI) neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupropion with (-)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, Coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.
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Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites.
The international journal of biochemistry & cell biology, 2015Co-Authors: Hugo R. Arias, Katarzyna M. Targowska-duda, Dominik Feuerbach, Krzysztof JozwiakAbstract:Abstract To characterize the interaction of Coronaridine congeners with human (h) α3β4 nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The Ca 2+ influx results established that Coronaridine congeners noncompetitively inhibit hα3β4 AChRs with the following potency (IC 50 's in μM) sequence: (−)-ibogamine (0.62 ± 0.23) ∼ (+)-catharanthine (0.68 ± 0.10) > (−)-ibogaine (0.95 ± 0.10) > (±)-18-methoxyCoronaridine [(±)-18-MC] (1.47 ± 0.21) > (−)-voacangine (2.28 ± 0.33) > (±)-18-methylaminoCoronaridine (2.62 ± 0.57 μM) ∼ (±)-18-hydroxyCoronaridine (2.81 ± 0.54) > (−)-noribogaine (6.82 ± 0.78). A good linear correlation ( r 2 = 0.771) between the calculated IC 50 values and their polar surface area was found, suggesting that this is an important structural feature for its activity. The radioligand competition results indicate that (±)-18-MC and (−)-ibogaine partially inhibit [ 3 H]imipramine binding by an allosteric mechanism. Molecular docking, molecular dynamics, and in silico mutation results suggest that protonated (−)-18-MC binds to luminal [i.e., β4-Phe255 (phenylalanine/valine ring; position 13′), and α3-Leu250 and β4-Leu251 (leucine ring; position 9′)], non-luminal, and intersubunit sites. The pharmacophore model suggests that nitrogens from the ibogamine core as well as methylamino, hydroxyl, and methoxyl moieties at position 18 form hydrogen bonds. Collectively our data indicate that Coronaridine congeners inhibit hα3β4 AChRs by blocking the ion channel's lumen and probably by additional negative allosteric mechanisms by interacting with a series of non-luminal sites.
Rhea C. Garcellano - One of the best experts on this subject based on the ideXlab platform.
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an iboga alkaloid chemotaxonomic marker from endemic tabernaemontana ternifolia with antitubercular activity
Natural Product Research, 2020Co-Authors: Rhea C. Garcellano, John R. Cort, Syed G. A. Moinuddin, Scott G. Franzblau, Alicia M. AguinaldoAbstract:Coronaridine (1) was isolated from the CH2Cl2 root extract of Tabernaemontana ternifolia. The structure of 1 was established from 1D- and 2D-NMR and HR-ESIMS experiments, and by comparison with rep...
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An iboga alkaloid chemotaxonomic marker from endemic Tabernaemontana ternifolia with antitubercular activity
2019Co-Authors: Rhea C. Garcellano, John R. Cort, Syed G. A. Moinuddin, Scott G. Franzblau, Alicia M. AguinaldoAbstract:Coronaridine (1) was isolated from the CH2Cl2 root extract of Tabernaemontana ternifolia. The structure of 1 was established from 1D- and 2D-NMR and HR-ESIMS experiments, and by comparison with reported spectroscopic data. To date, this is the first report of compound 1 from T. ternifolia, introduced as new Tabernaemontana species from Philippines in 2005 on the basis of morphological characters. Coronaridine, an iboga-type indole alkaloid, has been isolated from over 50 Tabernaemontana species and can thus be inferred as a chemotaxonomic marker of the genus. T. ternifolia has a distinct arrangement of leaves not known in the genus, but is variable in other genera. Its isolation from endemic T. ternifolia establishes its position in the genus and supports the claim that Coronaridine is a chemical marker of the genus Tabernaemontana. Interestingly, Coronaridine exhibited relatively weak activity against Mycobacterium tuberculosis H37Rv (MIC 82.64 μg/mL) (Rifampicin MIC 0.05 μg/mL).
Alicia M. Aguinaldo - One of the best experts on this subject based on the ideXlab platform.
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an iboga alkaloid chemotaxonomic marker from endemic tabernaemontana ternifolia with antitubercular activity
Natural Product Research, 2020Co-Authors: Rhea C. Garcellano, John R. Cort, Syed G. A. Moinuddin, Scott G. Franzblau, Alicia M. AguinaldoAbstract:Coronaridine (1) was isolated from the CH2Cl2 root extract of Tabernaemontana ternifolia. The structure of 1 was established from 1D- and 2D-NMR and HR-ESIMS experiments, and by comparison with rep...
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An iboga alkaloid chemotaxonomic marker from endemic Tabernaemontana ternifolia with antitubercular activity
2019Co-Authors: Rhea C. Garcellano, John R. Cort, Syed G. A. Moinuddin, Scott G. Franzblau, Alicia M. AguinaldoAbstract:Coronaridine (1) was isolated from the CH2Cl2 root extract of Tabernaemontana ternifolia. The structure of 1 was established from 1D- and 2D-NMR and HR-ESIMS experiments, and by comparison with reported spectroscopic data. To date, this is the first report of compound 1 from T. ternifolia, introduced as new Tabernaemontana species from Philippines in 2005 on the basis of morphological characters. Coronaridine, an iboga-type indole alkaloid, has been isolated from over 50 Tabernaemontana species and can thus be inferred as a chemotaxonomic marker of the genus. T. ternifolia has a distinct arrangement of leaves not known in the genus, but is variable in other genera. Its isolation from endemic T. ternifolia establishes its position in the genus and supports the claim that Coronaridine is a chemical marker of the genus Tabernaemontana. Interestingly, Coronaridine exhibited relatively weak activity against Mycobacterium tuberculosis H37Rv (MIC 82.64 μg/mL) (Rifampicin MIC 0.05 μg/mL).