Mechanisms of general anesthesia.
Although general anesthetics are often said to be nonspecific agents, it is likely that they act at a much more restricted set of target sites than commonly believed. The traditional view has been that the primary targets are lipid portions of nerve membranes, but recent evidence shows that the effects on lipid bilayers of clinically relevant levels of anesthetics are very small. Effects on most proteins are also small, but there are notable examples of proteins that are extremely sensitive to anesthetics and mimic the pharmacological profile of anesthetic target sites in animals. Such target sites are amphiphilic in nature, having both hydrophobic and polar components. The polar components appear to behave as good hydrogen-bond acceptors but poor hydrogen-bond donors. Although the targets can accept molecules with a wide variety of shapes and chemical groupings, they are unaffected by molecules exceeding a certain size. Overall, the data can be explained by supposing that the primary target sites underlying general anesthesia are amphiphilic pockets of circumscribed dimensions on particularly sensitive proteins in the central nervous system.
Franks
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NP
Biophysics Section, Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, UK.
Lieb
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WR
D000768:Anesthesia, General; D000777:Anesthetics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003243:Consciousness / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D008051:Lipid Bilayers / Q000737:chemistry; D008195:Lymnaea; D008563:Membrane Lipids / Q000737:chemistry; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000737:chemistry; D008954:Models, Biological; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000737:chemistry; D009474:Neurons / Q000187:drug effects; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013696:Temperature
D000777:Anesthetics; D008051:Lipid Bilayers; D008563:Membrane Lipids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins