Ligands, their receptors and … plasma membranes

Vauquelin, Georges; Packeu, Ann

doi:10.1016/j.mce.2009.07.022

Cited by 77 publications

(86 citation statements)

References 76 publications

(139 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Examples are provided for ligand-G-protein-coupled receptor tandems. An approach based on two-dimensional diffusion within the membrane has also been proposed to take place with several other ligand-receptor tandems [35,[95][96][97]99] 'microkinetic' model provides an elegant explanation for these observations. Drug partitioning may sometimes interfere with the correct interpretation of experimental observations and, to address this eventuality, it may be useful to compare the results from different experimental approaches.…”

Section: Drug Partitioningmentioning

confidence: 99%

Section: Drug Partitioningmentioning

confidence: 99%

“…These findings suggest that, from the 'microkinetic' perspective, clozapine functions very similarly to formoterol (Figure 1). By contrast, hydrophobic butyrophenones, such as haloperidol and spiperone, are likely to approach the D 2 receptor from within the membrane, like salmeterol [33][34][35].The accumulation of a drug within the membrane is accounted for by the partition coefficient, K p , which is the ratio at equilibrium between its concentration in the membrane and in the aqueous phase. Previously, K p values were obtained with octanol/buffer solvent systems as a surrogate model.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

View full text Add to dashboard Cite

The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

show abstract

Section: Drug Partitioningmentioning

confidence: 99%

Section: Drug Partitioningmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…4-mm MAS rotors were filled with the resulting pellets. Samples were kept in the rotors for both 1 H spectra were externally referenced to tetramethylsilane at 0 ppm.…”

Section: Methodsmentioning

confidence: 99%

“…Hence the interaction of a drug with the membrane is crucial for its efficacy. A high location probability in a particular part of a membrane and its orientation with respect to the membrane normal could well be relevant to how the drug is presented to the target protein's binding site (1,2). Cholesterol-rich microdomains ("lipid rafts") add another layer of complexity because the lateral organization of the membrane could well affect the concentration of a drug close to its target protein.…”

mentioning

confidence: 99%

Cholesterol and Lipid Phases Influence the Interactions between Serotonin Receptor Agonists and Lipid Bilayers

Batchelor

Windle

Buchoux

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Solid state NMR techniques have been used to investigate the effect that two serotonin receptor 1a agonists (quipazine and LY-165,163) have on the phase behavior of, and interactions within, cholesterol/phosphocholine lipid bilayers. The presence of agonist, and particularly LY-165,163, appears to widen the phase transitions, an effect that is much more pronounced in the presence of cholesterol. It was found that both agonists locate close to the cholesterol, and their interactions with the lipids are modulated by the lipid phases. As the membrane condenses into mixed liquid-ordered/disordered phases, quipazine is pushed up toward the surface of the bilayer, whereas LY-165,163 moves deeper into the lipid chain region. In light of our results, we discuss the role of lipid/drug interactions on drug efficacy.The majority of drug targets are membrane proteins. Hence the interaction of a drug with the membrane is crucial for its efficacy. A high location probability in a particular part of a membrane and its orientation with respect to the membrane normal could well be relevant to how the drug is presented to the target protein's binding site (1, 2). Cholesterol-rich microdomains ("lipid rafts") add another layer of complexity because the lateral organization of the membrane could well affect the concentration of a drug close to its target protein. This possibility is backed up by the observation that many chemicals, including drugs that target serotonin receptors, preferentially localize into these domains (3-5). Meanwhile, the location and activity of some membrane proteins, particularly G-protein-coupled receptors, seem to be affected by domains (6). Therefore, it is easy to imagine that a drug's efficacy may be limited by it partitioning into a different membrane domain than its target receptor. Furthermore, it is clear that many membrane proteins are modulated by the properties of the surrounding lipids. Hence, a drug has the potential to regulate a protein by altering these properties (7). This raises the intriguing possibility of a class of drugs that, instead of directly targeting a protein, target the membrane in which the protein resides. This route of action was first proposed as early as 1899 as a possible mechanism for general anesthetics, when it was noted that the potency of an anesthetic correlated very strongly with olive oil/water partitioning (8), yet drugs affecting membrane proteins via lipid interactions, so called "membrane-lipid therapy," have only relatively recently been explored (7, 9, 10).Some simple lipid mixtures have been used as models for in vivo microdomains. A particularly well studied mixture consists of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) Proton NMR and specifically magic angle spinning-assisted nuclear Overhauser enhancement spectroscopy (MAS-NOESY) experiments have proven to be an excellent tool for investigating, with atomic resolution, the location of small molecules embedded in lipid membranes (17)(18)(19)(20). However, these studies have been limited to binary...

show abstract

Case Study: Angiotensin Receptor Blockers (ARBs)

Vauquelin

2015

Thermodynamics and Kinetics of Drug Binding

View full text Add to dashboard Cite

Ligands, their receptors and … plasma membranes

Cited by 77 publications

References 76 publications

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Cholesterol and Lipid Phases Influence the Interactions between Serotonin Receptor Agonists and Lipid Bilayers

Case Study: Angiotensin Receptor Blockers (ARBs)

Contact Info

Product

Resources

About