Hydrophobic anesthetic

It is true that a more hydrophobic anesthetic is more potent, but not all hydrophobic substances are anesthetics. There exist substances such as 1,2-dichlorohexafluorocyclobutane and 2, 3-dichlorooctafluorobutane that would be predicted to be anesthetic based on their hydrophobicity, but that do not have anesthetic properties. These substances are called either non-anesthetics or non-immobilizers depending on the behaviors that have been tested and found lacking (Koblin et ak, 1994). 

Note that the relative spatial arrangement of the phenyl, amine, and hydroxyl functionahties are identical for (R)-alprenolol and (5)-sotalol. In addition to P-blocking activities, some of these compounds also possess potent local anaesthetic activity (see Anesthetics). The membrane stabilizing activity, however, is not stereoselective and correlates directly with the partition coefficient (hydrophobicity) of the compound. 

It is expected that the neutral species of the anesthetics can penetrate more deeply into the hydrophobic bilayer interior than the cationic ones. From the H and C NMR, we have demonstrated that the neutral species, DEC and PRC, are trapped deeply in the bilayer DEC can penetrate into the hydrophobic core of the bilayer, zone III, and PRC can penetrate into the inside of the bilayer preferentially trapping from zone II to the middle of zone III [48]. This information is valuable in the sense that it is difficult to observe the NMR signal of the neutral species in water because of the extremely low solubility. The preferential location is in accordance with the solubility in water the neutral species of DEC and PRC, sparingly soluble in water, are expected to favor the hydrophobic bilayer interior. 

Although the contribution is rather small, the partial discharging of the anesthetics in membranes can be important in the mechanism of the anesthetic action. The most plausible mechanism can be summarized as only a small portion of the cationic species are neutralized (deprotonated) at the bilayer surface and the neutral species are deeply penetrated and widely distributed in the hydrophobic bilayer interior, while the cationic species still remain at the hydrophilic bilayer surface where the hydration is significant. 

Machleidt H, Roth S, Seeman P. 1972. The hydrophobic expansio of erythrocyte membranes by phenol anesthetics. Biochim Biophys Acta 255 178-189. 

A matter of philosophical rather than practical significance is the close similarity in the optimal hydrophobicity for the random-walk process in plants and animals. In a series of papers dating bact to 1968, Hansch ( 3) has shown that drugs acting rather non-specifically in the animal central nervous system, such as anesthetics and barbiturates, also have an optimal log P in the 2.0 to 2.5 range (Table V). 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

The answer is E. Anesthetics are highly lipid-soluble and experiments with isolated membranes indicate that these molecules can dissolve in the hydrophobic center of the membrane bilayer. This causes a measurable increase in the membrane fluidity by disrupting the packed structure of phospholipids tails. This is considered to be the main, direct mechanism by which this class of drugs inhibits neurotransmission (pain sensations) in neurons. Hallucinogens and opiates may also affect membrane fluidity, but their effects occur by indirect mechanisms, resulting from changes in the protein or lipid composition of the membranes. 

Several general anesthetics (isoflurane, ketamine, thiopental, etomidate) have one or more chiral carbons and thus exist as pairs ot stereoisomers. In many cases one stereoisomer is more potent than the other at providing anesthesia despite little difference in pharmacokinetics (Christensen Lee, 1973 Benthuysen et ak, 1989 Harris et ak, 1992 Dickinson et ak, 1994). The stereoisomers have equal hydrophobic properties and partition equally into the membrane. 

As the carbon chain length in an anesthetic series increases (for example in the family of long chain alcohols), a substance becomes more hydrophobic and should be a more potent anesthetic. This is true only until a specific size cut off when the next larger agent becomes ineffective as an anesthetic (Franks Lieb 1986). 

While current observations do not rule out that anesthetics may require a hydrophobic environment near the site of their action, they do suggest that various agents may also have distinct interactions with tissues. For example, enantiomers of newer agents have selec-... 

Hille B Local anesthetics Hydrophilic and hydrophobic pathways for the drug-receptor reactions. J Gen Physiol 1977 69 497. [PMID 300786]... 

The induction of unconsciousness may be the result of exposure to excessive concentrations of toxic solvents such as carbon tetrachloride or vinyl chloride, as occasionally occurs in industrial situations (solvent narcosis). Also, volatile and nonvolatile anesthetic drugs such as halothane and thiopental, respectively, cause the same physiological effect. The mechanism(s) underlying anesthesia is not fully understood, although various theories have been proposed. Many of these have centered on the correlation between certain physicochemical properties and anesthetic potency. Thus, the oil/water partition coefficient, the ability to reduce surface tension, and the ability to induce the formation of clathrate compounds with water are all correlated with anesthetic potency. It seems that each of these characteristics are all connected to hydrophobicity, and so the site of action may be a hydrophobic region in a membrane or protein. Thus, again, physicochemical properties determine biological activity. 

The pharmacological activity of LAs is determined by several physicochemical properties including lipophilicity, protein binding, and pKa which can be explained by their mechanism of action. A general structure - activity relationship was described by Courtney and Strichartz (1987), according to which an increase in the hydrophobicity leads to a parallel increase in anesthetic... 

A means to avoid such tedious optimization can be envisaged by employing stoichiometric monomers to develop strong interactions with the template as mentioned above. The other way is to incorporate hydrophilic comonomers (2-hydroxyethyl methacrylate (HEMA), acrylamide) or cross-linkers (pentaerythri-toltriacrylate, methylene bisacrylamide) in the polymer. This results in an increase of the hydrophilicity of the polymer. Indeed, the use of HEMA for a MIP directed towards the anesthetic bupivacaine resulted in high imprinting factors due to reduced non-specific hydrophobic adsorption in aqueous buffer. This was not the case when HEMA was omitted from the polymerization mixture [27]. These conditions were exploited for the direct and selective extraction of bupivacaine from blood plasma samples. 

Fluorescence probes are frequently used to study changes in membrane organization and membrane fluidity induced by anesthetics, various drags, and insecticides. This technique measures fluidity as the rate and extent of phospholipid acyl chain excursion away from some initial chain orientation during the lifetime of the excited fluorescence state. Special techniques even allow the place of interaction to be localized, i.e. to the outer membrane region, the hydrophobic area, or the embedded proteins. 

This question of direct interaction with nerve proteins or indirect interaction via membrane perturbation has also been tackled by ESR spectroscopy. Two types of labeling have been used fatty acids for lipid labeling and maleimide for frog nerve proteins. The anesthetics used were halothane as an example of a general anesthetic and procaine, lidocaine, and tetracaine as examples of local anesthetics. The latter interact primarily with head groups but can also merge into the hydrophobic hydrocarbon... 

The slope of the regression line implies that the MAC (minimal alveolar concentration effective in 50 percent of animals) is inversely proportional to partition coefficient or potency is directly proportional to partition coefficient. The Meyer-Overton correlation suggests that the site at which anesthetics bind is primarily a hydrophobic environment. Although a wide variety of compounds lie on the Meyer-Overton correlation line, there are many compounds that do not. This suggests that the chemical properties of the anesthetic site differ from those of olive oil. 

Interesting calculations have been carried out by others dealing with the interaction of anesthetic molecules on lipids and proteins. For example, at the MAC, the concentration of anesthetic molecules in the hydrophobic phase is approximately 50 mM. Assuming that the anesthetic molecules are uniformly distributed throughout the lipid bilayer of a cell membrane of thickness 50 A, there would be only one anesthetic molecule for every 60 lipid molecules (i.e., 1.5 percent of the molecules in the membrane and only 0.5 percent of the membrane volume). Under these circumstances, the anesthetic molecules would be distributed too diffusely to have a significant effect on membrane status. If, however, anesthetic molecules became preferentially located adjacent to a protein, then a local effect on protein function might occur. 

Because of cocaine s toxicity and addictive properties, a search began for synthetic substitutes for cocaine. In 1905, procaine was synthesized and became the prototypic local anesthetic for half a century. Newer derivatives include mepivacaine and tetracaine (Figure 13.1). Briefly, the SAR of local anesthetics revolves around their hydrophobicity. Association of the drug at hydrophobic sites, such as the sodium channel, is believed to prevent the generation and conductance of a nerve impulse by interfering with sodium permeability (i.e., elevating the threshold for electrical excitability). 

Comparative analysis of known sodium channel blockers has resulted in several somewhat distinct models [88-91]. These models suggest that local anesthetic and anticonvulsant sodium channel blockers share a pharmacophore consisting of a hydrophobic group (typically an aryl ring) separated by 5-6 A from a hydrogen bond acceptor-donor group. 

Hille, B. 1977. Local anesthetics hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69, 497-515. 

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