Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

Sherwood, Alexander M.; Crowley, Rachel Saylor; Paton, Kelly F.; Biggerstaff, Andrew; Neuenswander, Benjamin; Day, Victor W.; Kivell, Bronwyn M.; Prisinzano, Thomas E.

doi:10.1021/acs.jmedchem.7b00148

Cited by 30 publications

(47 citation statements)

References 55 publications

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“…Notably, a thiocyanate analogue of SalA, RB-64, was shown to strongly bias toward G protein-coupled signaling. 18 While many semisynthetic analogues of SalA have been explored, the most prolific investigators recently noted that its “chemical liabilities...narrow the available pool of viable chemical transformations.” 13 …”

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confidence: 99%

Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist

et al. 2017

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Salvinorin A (SalA) is a plant metabolite that agonizes the human kappa-opioid receptor (κ-OR) with high affinity and high selectivity over mu- and delta-opioid receptors. Its therapeutic potential has stimulated extensive semisynthetic studies and total synthesis campaigns. However, structural modification of SalA has been complicated by its instability, and efficient total synthesis has been frustrated by its dense, complex architecture. Treatment of strategic bonds in SalA as dynamic and dependent on structural perturbation enabled the identification of an efficient retrosynthetic pathway. Here we show that deletion of C20 simultaneously stabilizes the SalA skeleton, simplifies its synthesis, and retains its high affinity and selectivity for the κ-OR. The resulting 10-step synthesis now opens the SalA scaffold to deep-seated property modification. Finally, we describe a workflow to identify structural changes that retain molecular complexity, but reduce synthetic complexity—two related, but independent ways of looking at complexity.

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confidence: 99%

Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist

et al. 2017

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“…Compounds containing an acetate group are liable to metabolism through de‐acetylation. Protection of acetyl group was described by Sherwood et al where the acetyl group was bioisosterically replaced by spirobutyrolactone to prevent the rapid deacetylation and deactivation process.…”

Section: Effect Of Chemical Structure On Physicochemical Properties Amentioning

confidence: 99%

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

Farouk

Shamma

2019

Archiv der Pharmazie

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The chemical structure of a drug molecule affects its physicochemical properties and subsequent biological activities. Many pharmacologically active molecules fail to reach the market or have an inconvenient route of administration due to their chemical structure. This is especially important with the recent tendency to develop drug candidates beyond the drug-likeness space for addressing difficult targets such as protein-protein interfaces. The objective of this review is to discuss chemical and pharmaceutical approaches for circumventing structure-related problems and achieving acceptable ADME-Tox properties. The chemical structure-associated limitations are critically discussed. Chemical modifications and pharmaceutical technology applications for improving drug-likeness are illustrated. Attention is paid to modern therapeutic candidates and targets. In conclusion, chemical modifications as well as nanotechnology applications can be used effectively to enhance absorption, permeability, and selective distribution to a body compartment, to improve drug specificity, to limit off-target toxicity as well as to enhance stability and to protect against metabolism. The nano-technology-based solutions are relatively easier to develop over a new molecular entity, but adopting the chemical approach is more established in terms of safety, quality control, and regulatory assessment methods. K E Y W O R D Sblood-brain barrier, cancer tissue delivery, drug delivery, drug targeting, protein-protein interaction

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“…The C2 acetate in 1 or the methoxymethyl group in 3 is required for activity, 7 further exemplified by 4 , which is completely inactive. 9 Semisynthetic manipulations at the C4 carbomethoxy on 1 have been surprisingly difficult and limited semisynthetic data at this position exists. However, some analogues with C4-modifications have been evaluated for their KOR activity, including carboxylic acid 5 .…”

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Modular Approach to pseudo-Neoclerodanes as Designer κ-Opioid Ligands

et al. 2017

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Informed by previous semisynthetic work on salvinorin A, a modular total synthesis has been developed capable of producing novel compounds targeting the kappa opioid receptor. The strategy has permitted the deliberate simplification and introduction of functionality about the target molecule to provide access to molecular features on salvinorin A otherwise unattainable by semisynthesis. Using this approach, a potent pseudo-neoclerodane kappa opioid receptor ligand (2) has been realized.

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Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

Cited by 30 publications

References 55 publications

Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist

Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent κ-OR Agonist

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

Modular Approach to pseudo-Neoclerodanes as Designer κ-Opioid Ligands

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