Receptor medium effects

Zwanzig, R. (1990). Diffusion-controlled ligand binding to spheres partially covered by receptors an effective medium treatment, Proc. Natl. Acad. Sci. USA, 87, 5856-5857. 

The medium may have a marked effect on the shape of receptor molecules itself. Shape modifications could strongly influence their substrate binding properties, for instance in the case of amphiphilic cyclophane receptors subjected to hydrophobic-hydrophilic factors in aqueous solution. Such medium effects in action are visualized by the solid state structures of two different forms of the water-soluble hexasodium salt of the macrobicyclic cyclophane 66, which could be crystallized in two very different shapes an inflated cage structure 71 building up cylinders disposed in a hexagonal array and a flattened structure 72 stacked in molecular layers separated by aqueous layers in a lamellar arrangement [4.73]. These two... 

Data in Table 2 reveal that with a few exceptions, the stability of the complexes is enthalpy controlled and entropy destabilised. As previously stated, the variations observed in the thermodynamics of complexation of these systems as a result of the medium effect are the result of the solvation changes that the reactants (anion and receptor) and the product (complex anion) undergo in moving from one medium to another. This issue will be carefully addressed in the next section. 

While the previous receptors are typically used in organic solvents, except for the cyclodextrins, there are special cases of cyclophane receptors supphed with peripheral charges (ammonium units) (107—12) or ionizable groups (carboxylate functions) (113,114) (Fig. 17) to allow substrate recognition, as in nature, in an aqueous medium, profiting from the solvophobic effects of water (115). 

The mechanisms by which the taste (and also the olfactory) system senses chemical compounds is assumed to occur by way of a chemoreceptory system that interacts effectively with a broad, structural variety of stimulant molecules, by means of a receptor epithelium consisting of the mosaic of adjacent, peripheral membranes of many receptor cells, exposed to a medium carrying stimulus molecules. A receptor cell is conveniently and, for our present purpose, sufficiently defined as a cell equipped to interact, according to some mechanism, with stimulus molecules, to convert the effect of this interaction into a signal, and to project this signal into the system. The taste receptor is thus a differentiated, epithelial cell synaptically contact-... 

Inter- and intramolecular force effects. These effects result either from the interactions between the substituent and its immediate surroundings such as the medium, a surface or a receptor site, or from the effect of the substituent on the interactions of the skeletal group G and the active site Y with their surroundings. 

There have been several studies that underscore the importance of unbound concentration in cell-based studies of receptor function. In a model study of the effect of plasma protein binding on the renal transport of organic anions using the expression of various organic anion transporters (OATPs) in Xenopus oocytes, the transport of ochratoxin A, methotrexate, and estrone sulfate was found to be strongly inhibited by the addition of human serum albumin to the culture medium [16]. Similarly, the addition of oq-acid glycoprotein was found to reverse the blockade of sodium-ion current by cocaine in a preparation of cardiac myocytes [17]. 

An important question arises about the effects of phospholipid composition and the function of membrane-bound enzymes. The phospholipid composition and cholesterol content in cell membranes of cultured cells can be modified, either by supplementing the medium with specific lipids or by incubation with different types of liposomes. Direct effects of phospholipid structure have been observed on the activity of the Ca2+-ATPase (due to changes in the phosphorylation and nucleotide binding domains) [37]. Evidence of a relationship between lipid structure and membrane functions also comes from studies with the insulin receptor [38]. Lipid alteration had no influence on insulin binding, but modified the kinetics of receptor autophosphorylation. 

These medications cannot be dosed solely based on their dopamine receptor blocking potency, because they also have effects on other receptors that must be factored into their dosing (see Table 4.6). For example, it is not unusual to begin treatment of a psychotic patient with a 5 mg dose of haloperidol. In terms of dopamine receptor blocking potency, 5 mg of haloperidol is more or less equivalent to 500 mg of chlorpromazine. If a patient were immediately treated with 500 mg of chlorpromazine, however, he/she would likely have side effect problems such as dizziness and excessive sedation. This is because the medications with the lowest dopamine receptor blocking potency are the most potent at other receptor systems responsible for these side effects. (See Table 4.7) The evolution of antipsychotics from low to medium to high potency has been driven not only by the desire to find... 

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