Unconventional Alkoxylation of Pyrazino[2,3‐c][1,2,6]thiadiazine 2,2‐Dioxides Mediated by N‐Halosuccinimides.

Campillo, Nuria E.; Páez, Juan A.; Goya, Pilar

doi:10.1002/chin.200243204

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“…4,5,32,33 Observing natural 2a near one of its two lowest energy conformations (Figure 3), it is apparent that a near bilateral symmetry exists with few steric differences on either side of the plane as was noted when the activity of the enantiomers of 2a was initially reported. 5,34 This conformation is generally observed in docked models of epibatidine with nicotinic receptors and in an X-ray structure with an acetylcholine binding protein (2BYQ). [35][36][37] On the other hand, 1 is significantly enantioselective with eudismic ratios averaging 30-50 and its structure lacks any significant bilateral symmetry.…”

Section: Structure-activity Relationships Between Phantasmidine and Kmentioning

confidence: 87%

Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine

et al. 2018

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Phantasmidine, a rigid congener of the well-known nicotinic acetylcholine receptor agonist epibatidine, is found in the same species of poison frog ( Epipedobates anthonyi). Natural phantasmidine was found to be a 4:1 scalemic mixture, enriched in the (2a R,4a S,9a S) enantiomer by chiral-phase LC-MS comparison to the synthetic enantiomers whose absolute configurations were previously established by Mosher's amide analysis. The major enantiomer has the opposite S configuration at the benzylic carbon to natural epibatidine, whose benzylic carbon is R. Pharmacological characterization of the synthetic racemate and separated enantiomers established that phantasmidine is ∼10-fold less potent than epibatidine, but ∼100-fold more potent than nicotine in most receptors tested. Unlike epibatidine, phantasmidine is sharply enantioselective in its activity and the major natural enantiomer whose benzylic carbon has the 4a S configuration is more active. The stereoselective pharmacology of phantasmidine is ascribed to its rigid and asymmetric shape as compared to the nearly symmetric conformations previously suggested for epibatidine enantiomers. While phantasmidine itself is too toxic for direct therapeutic use, we believe it is a useful platform for the development of potent and selective nicotinic agonists, which may have value as pharmacological tools.

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Section: Structure-activity Relationships Between Phantasmidine and Kmentioning

confidence: 87%

Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine

et al. 2018

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Unconventional Alkoxylation of Pyrazino[2,3‐c][1,2,6]thiadiazine 2,2‐Dioxides Mediated by N‐Halosuccinimides.

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 1 publication

References 1 publication

Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine

Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine

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