Intramolecular Interactions Encoded in Lipophilicity: Their Nature and Significance

Testa, B.; Carrupt, Pierre‐Alain; Gaillard, Patrick; Tsai, Ruey-Shiuan

doi:10.1002/9783527614998.ch4

Cited by 41 publications

(25 citation statements)

References 23 publications

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“…For instance, although epimers (e.g., KK-148 and KK-150) and regioisomers (KK-123 and MQ-127) may have different measured logP values (Testa et al, 2008), any logP differences within such pairs will be small relative to those caused by structural changes such as removal or addition of a hydroxyl group. Taken together, the results in Figure 3G, indicate that although logP is unlikely to dictate Golgi localization, stereochemical differences in structure clearly affect Golgi localization.…”

Section: Resultsmentioning

confidence: 99%

A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition

et al. 2016

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Anesthetic, GABA-active neurosteroids potently augment GABAA receptor function, leading to important behavioral consequences. Neurosteroids and their synthetic analogues are also models for a wide variety of cell-permeant neuroactive compounds. Cell permeation and compartmentalization raise the possibility that these compounds’ actions are influenced by their cellular partitioning, but these contributions are not typically considered experimentally or therapeutically. To examine the interplay between cellular accumulation and pharmacodynamics of neurosteroids, we synthesized a novel chemical biology analogue (bio-active, clickable photolabel) of GABA-active neurosteroids. We discovered that the analogue selectively photo-labels neuronal Golgi in rat hippocampal neurons. The active analogue’s selective distribution was distinct from endogenous cholesterol and not completely shared by some non-GABA active, neurosteroid-like analogues. On the other hand, the distribution was not enantioselective and did not require energy, in contrast to other recent precedents from the literature. We demonstrate that the soma-selective accumulation can act as a sink or source for steroid actions at plasma-membrane GABA receptors, altering steady-state and time course of effects at somatic GABAA receptors relative to dendritic receptors. Our results suggest a novel mechanism for compartment-selective drug actions at plasma-membrane receptors.

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Section: Resultsmentioning

confidence: 99%

A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition

et al. 2016

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“…The applications of lipophilicity include diverse fields such as drug design for targeted delivery, liquidliquid extraction of compounds, quantitative structure-activity relationships, and intra-and intermolecular forces of recognition [74][75][76]. Although a recent theory proposed that drug transport is only carrier-mediated and new transporters will be discovered that possess transport characteristics ascribed to passive diffusion [77,78], it is more probable that passive and carriermediated processes coexist [79][80][81].…”

Section: Introductionmentioning

confidence: 99%

Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

Mazák

Noszál

2016

Journal of Pharmaceutical and Biomedical Analysis

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“…This clearly illustrates that obtaining the appropriate form of the tautomer improves the quality of the property prediction. The last example concerns the intramolecular H-bond due to the tautomeric interchange [270,271]. López-Rodríguez et al [271] studied the prototropic equilibrium in the series of serotonin 5-HT4 receptor ligands.…”

Section: Tautomerism and Bindingmentioning

confidence: 99%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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The effect of weak intermolecular interactions on the binding affinity between ligand-protein complexes plays an important role in stabilizing a ligand at the interface of a protein structure. In this review article, we will explore the different ways of taking into account these interactions, mainly intramolecular hydrogen bonds, in docking calculations. Their possible limitations and their suitable application domains are highlighted. Inspection of the outliers of this study probed very stimulating, as it provides opportunities and inspiration to medicinal chemists, being a reminder of the impact that minimal chemical modifications can have on biological activities.

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Intramolecular Interactions Encoded in Lipophilicity: Their Nature and Significance

Cited by 41 publications

References 23 publications

A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition

A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition

Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

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