Weak Intermolecular Associations and Anesthesia

THE right structure and functioning of biologic macromolecules are ensured by a great number of intermolecular associations, hydrogen bonds, and van der Waals associations. Because general anesthesia must be reversible its action is likely to consist in the replacement or perturbation of weak hydrogen bonds or van der Waals associations by others involving the anesthetic. A qualitative understanding of general anesthesia can be based on this idea. Hydrogen bonds (H-bonds) are ubiquitous in nature. It is no overstatement to say that life would not be possible without them. Water would not be liquid at ambient temperature; water, proteins, nucleic acids, and saccharides that are the main constituents of living bodies would not have their specific structures that enable them to fulfill their functions. Nature uses H-bonds whenever a certain degree of stability is needed as well as versatility. All this naturally applies to the constituents of the nervous system. Moreover, as anesthesia represents an interference with the normal functioning of the nervous system, it would be surprising if H-bonds were not involved with the mechanism of anesthesia. This does not mean, however, that other types of intermolecular associations are not involved. This view took a long time to become widespread. The fact that general anesthetics are usually lipid and not water soluble and that there is a correlation between lipid solubility and anesthetic potency (the Meyer-Overton rule) focused the attention of researchers on nonpolar interactions in the hydrophobic parts of the lipid cell membrane and, later, of proteins. Excellent critical reviews on this evolution are available. The most important fact for the present discussion is that general anesthesia occurs through an interplay of intermolecular interactions without proper chemical reactions, although certain anesthetics metabolize after exerting their action. So the question is this: what kind of intermolecular interactions are involved? At this point one must remember the extreme variety of the chemical structure of anesthetics. Nearly all molecules have some anesthetic potency. Among these are rare gases, saturated hydrocarbons, alcohols, ethers, ketones, and halocarbons, among others. A chemist could hardly admit that they all exert their action by the same “unitary” mechanism. The differences should be looked for in the nature of intermolecular interactions that are involved. A pluralistic theory was proposed. Present research tends to locate the site of action of anesthetics in the neurotransmitter receptors at the synapse. The receptors are proteins, possibly glycoproteins or lectins. The structure of these macromolecules and their conformations that are adapted to their functions are ensured by a great number of intermolecular interactions, van der Waals or H-bonding. Some anesthetics, like xenone can be supposed to use only van der Waals interactions where the main factor is polarizability. However, most of them possess atoms or groups that can act as proton donors or acceptors, or both. This is why the role of H-bonding seems to be inevitable. A typical example are the widely used anesthetics which are halocarbons containing the “acidic hydrogen” like chloroform, halothane, methoxyflurane, isoflurane, enflurane, and others. Such molecules can form Hbonds as weak proton donors. Evidence has been provided by infrared spectroscopic methods that these weak H-bonds can alter significantly the free/H-bonded equilibrium even in much stronger H-bonds of the O-H. :O or N-H. :O types. The reasons for this were investigated by quantum chemical-thermodynamic calculations. A correlation was found between the H-bond bond breaking ability of acidic hydrogen containing halocarbons and their anesthetic potency. The idea that the formation and perturbation of Hbonds plays a role in the mechanism of general anesthesia was advocated in a series of publications from the author’s laboratory. More recently Brockerhoff et al. and Abraham et al. assessed the role of H-bonding in the mechanism of general anesthesia. Then the next question is this: what type of H-bonds are likely to be affected by anesthetics? There exists a great variety of H-bonds; their energy (enthalpy) varies from 1 to approximately 50 kcal/M. From the point of view of the living organism the weaker ones are the most important. Anesthetic action must, of course, be reversible, so the perturbation that it entails must fall into the range of thermal fluctuations or other weak—van der Waals—interactions. Because weak H-bonds are long range interactions falling off with r , they are still significant at H. X distances of 3.0 or 3.5 Å. They have energies (enthalpies) on the order of 1 or 2 kcal/M. Jeffrey and Saenger devote a chapter to weak H-bonding interactions in biologic systems: “Weak HydrogenBonding Interactions Formed by C-H Groups as Donors Professor Emeritus, Département de chimie, Université de Montréal, Montréal, Quebec.