Synthesis of (−)-Picrotoxinin by Late-Stage Strong Bond Activation

Crossley, Steven W. M.; Tong, Guanghu; Lambrecht, Michael J.; Burdge, Hannah E.; Shenvi, Ryan A.

doi:10.1021/jacs.0c05042

Cited by 36 publications

(36 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Picrotoxin is a plant-derived product, with a universal efficacy as GABA A R’s chloride channel blocker. Picrotoxin is found naturally in the Anamirta Cocculus plant, although it can be synthesized chemically [ 137 , 138 ]. It has been utilized as a CNS stimulant, and antidote for poisoning by CNS depressants and barbiturates [ 139 ].…”

Section: Molecular Pharmacology Of Gaba a Receptorsmentioning

confidence: 99%

GABAA receptors: structure, function, pharmacology, and related disorders

Ghit

Assal

Al‐Shami

et al. 2021

Journal of Genetic Engineering and Biotechnology

153

115

View full text Add to dashboard Cite

Background γ-Aminobutyric acid sub-type A receptors (GABAARs) are the most prominent inhibitory neurotransmitter receptors in the CNS. They are a family of ligand-gated ion channel with significant physiological and therapeutic implications. Main body GABAARs are heteropentamers formed from a selection of 19 subunits: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) which result in the production of a considerable number of receptor isoforms. Each isoform exhibits distinct pharmacological and physiological properties. However, the majority of GABAARs are composed of two α subunits, two β subunits, and one γ subunit arranged as γ2β2α1β2α1 counterclockwise around the center. The mature receptor has a central chloride ion channel gated by GABA neurotransmitter and modulated by a variety of different drugs. Changes in GABA synthesis or release may have a significant effect on normal brain function. Furthermore, The molecular interactions and pharmacological effects caused by drugs are extremely complex. This is due to the structural heterogeneity of the receptors, and the existence of multiple allosteric binding sites as well as a wide range of ligands that can bind to them. Notably, dysfunction of the GABAergic system contributes to the development of several diseases. Therefore, understanding the relationship between GABAA receptor deficits and CNS disorders thus has a significant impact on the discovery of disease pathogenesis and drug development. Conclusion To date, few reviews have discussed GABAA receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABAARs, as well as shedding light on the most common associated disorders.

show abstract

Section: Molecular Pharmacology Of Gaba a Receptorsmentioning

confidence: 99%

GABAA receptors: structure, function, pharmacology, and related disorders

Ghit

Assal

Al‐Shami

et al. 2021

Journal of Genetic Engineering and Biotechnology

153

115

View full text Add to dashboard Cite

show abstract

“…We recently reported a synthesis of PXN and a close analog, 5‐methyl‐PXN [17] . The methyl group enabled quick access to picrotoxinin chemical space (9 steps, 8 % overall yield) and retained potent antagonism of rat GABA A receptors.…”

Section: Figurementioning

confidence: 99%

“…The methyl group enabled quick access to picrotoxinin chemical space (9 steps, 8 % overall yield) and retained potent antagonism of rat GABA A receptors. Furthermore, 5‐methyl‐PXN hydrolyzed more slowly: about 40 % the rate of PXN using pH 8.0 phosphate buffer in D 2 O (8.2 pH*) [17, 18] . We were curious to understand the effect of the 5‐methyl substituent on rate and sought to establish a competent 1 H NMR assay for PXN itself, to better characterize the intermediates.…”

Section: Figurementioning

confidence: 99%

Revision of the Unstable Picrotoxinin Hydrolysis Product

Tong

Shenvi

2021

Angewandte Chemie

Self Cite

View full text Add to dashboard Cite

The plant metabolite picrotoxinin (PXN) is a widely used tool in neuroscience for the identification of GABAergic signaling. Its hydrolysis in weakly alkaline media has been observed for over a century and the structure of the unstable hydrolysis intermediate was assigned by analogy to the degradation product picrotoxic acid. Here we show this assignment to be in error and we revise the structure of the hydrolysis product by spectroscopic characterization in situ. Counterintuitively, hydrolysis occurs at a lactone that remains closed in the major isolable degradation product, which accounts for the longstanding mistake in the literature.

show abstract

“…Recently, a cryo‐EM structure of PXN bound to the human α1β3γ2 GABA A receptor demonstrated its binding pose between the M2 helices of the ion channel, and elucidated the basis for its long‐range allosteric effects on GABA binding 28 . Its high activity towards RDL receptors ( Drosophila RDL, IC 50 ~ 50 n m ) 29,30 might provide PXN potential as an insecticide, if its mammalian toxicity can be reduced 31–33 . Attempts to broaden this selectivity window through semi‐synthesis have not been successful, but, remarkably, picrodendrin congeners (Figure 1) have demonstrated a promising reversal of potencies.…”

Section: Gabaar Antagonistsmentioning

confidence: 99%

“…An extra methyl group proved key to this transformation, and its excision could be accomplished in a series of CH and CC bond cleavages, leading to PXN in a total of 13 steps from carvone. However, retaining this methyl group significantly shortened access to functional picrotoxinin chemical space: 5‐Me‐PXN antagonizes GABA A R, albeit at reduced potency, but also exhibits greater hydrolytic stability compared to PXN 33 . This analog retains all the complexity of PXN itself, retains its function, and retains its overall molecular properties.…”

Section: Chemical Syntheses Of Select Cys‐loop Receptor Antagonistsmentioning

confidence: 99%

Change the channel: CysLoop receptor antagonists from nature

Tong

Baker

Shenvi

2020

Pest Management Science

Self Cite

View full text Add to dashboard Cite

Vertebrate and invertebrate ligand‐gated ion channels (LGICs) exhibit significant structural homology and often share ligands. As a result, ligands with activity against one class can be brought to bear against another, including for development as insecticides. Receptor selectivity, metabolism and distribution must then be optimized using chemical synthesis. Here we review natural products (NPs) that ligate and inhibit the Cys‐loop family of LGICs, which benefit from the unique physicochemical properties of natural product space but often present a high synthetic burden. Recent advances in chemical synthesis, however, have opened practical entries into these complex structures, several of which are highlighted. © 2020 Society of Chemical Industry

show abstract

Synthesis of (−)-Picrotoxinin by Late-Stage Strong Bond Activation

Cited by 36 publications

References 42 publications

GABAA receptors: structure, function, pharmacology, and related disorders

GABAA receptors: structure, function, pharmacology, and related disorders

Revision of the Unstable Picrotoxinin Hydrolysis Product

Change the channel: CysLoop receptor antagonists from nature

Contact Info

Product

Resources

About