Because a wide variety of structurally unrelated compounds obey the Meyer-Overton rule, it has been reasoned that all anesthetics are likely to act at the same molecular site (referred to as the unitary theory of anesthesia).
Because solubility in a specific solvent strongly correlates with anesthetic potency, the anesthetic target site was assumed to be hydrophobic in nature.
The octanol–water partition coefficient best correlates with anesthetic potency, suggesting that the anesthetic site is likely to be amphipathic, having both polar and nonpolar characteristics.
Exceptions to the Meyer-Overton Rule
Compounds exist that are structurally similar to halogenated anesthetic, barbiturates, and neurosteroids yet are convulsants rather than anesthetics.
In several homologous series of anesthetics, anesthetic potency increases with increasing chain length until a certain critical chain length is reached. Beyond this critical chain length, compounds are unable to produce anesthesia even at the highest attainable concentrations (cutoff effect).
The observation that enantiomers (mirror-image compounds) of anesthetics differ in their potency as anesthetics is a deviation from the Meyer-Overton rule.
In defining the molecular target(s) of anesthetic molecules, one must be able to account both for the Meyer-Overton rule and for the well-defined exceptions to this rule.
It has sometimes been suggested that a correct molecular mechanism of anesthesia should also be able to account for pressure reversal (the phenomenon whereby the concentration of a given anesthetic needed to produce anesthesia is greatly increased if the anesthetic is administered to an animal under hyperbaric conditions). However, evidence suggests that pressure reverses anesthesia by producing excitation that physiologically counteracts anesthetic depression rather than by acting as an anesthetic antagonist at the anesthetic site of action.
Lipid versus Protein Targets. Anesthetics might interact with several possible molecular targets to produce their effects on the function of ion channels and other proteins.
Lipid Theories of Anesthesia. The lipid theory of anesthesia postulates that anesthetics dissolve in the lipid bilayers of biological membranes and produce anesthesia when they reach a critical concentration in the membrane. Yet no lipid theory can plausibly explain all anesthetic pharmacology, and most investigators do not consider lipids as the most likely target of general anesthetics.
Protein Theories of Anesthesia. The Meyer-Overton rule could also be explained by the direct interaction of anesthetics with hydrophobic sites on proteins.
Direct interactions of anesthetic molecules with proteins not only satisfies the Meyer-Overton rule but would also provide the simplest explanation for compounds that deviate from this rule.
Protein-binding sites for anesthetics could also explain the convulsant effects of some polyhalogenated alkanes.