Meyer-Overton Correlation - OpenAnesthesia

Key Points

The Meyer-Overton correlation proposes the existence of a linear relationship between the lipophilic nature of anesthetic medications and their biological activity.¹
Local anesthetics act through several proposed mechanisms, one of which is membrane-mediated activity, the mechanism underlying the Meyer-Overton correlation.²
Anesthetic drugs have a wide range of proposed targets, which include lipids, membrane proteins, and ion channels.³

Emergence of the Meyer-Overton Correlation

In the early 1900s, scientists Charles Ernest Overton and Hans Horst Meyer conducted experiments with anesthetic drugs that yielded results suggesting a linear relationship between the oil-partition properties of those drugs and their potency relative to concentration.⁴ For example, as the oil-partition coefficient of an anesthetic increases, the potency also increases in a predictable fashion.
Significant implications of these experimental results include:
- A historically early experimental record suggesting a unifying theme of drug action related to drug properties, as well as the drug mechanism of action.⁴
- The experiment’s findings popularized the notion that lipids were the primary targets of anesthetic drugs.⁴ Popular proposed mechanisms included cell membrane expansion, cell membrane fluidity increase, and lateral surface pressure increase.⁴
- Because these outcomes are based on early tests of anesthetic mechanisms of action, the experiments’ findings have been subject to the continually evolving body of research on anesthetic agents.

Role In Drug Mechanisms of Action

The Meyer-Overton correlation was formulated in the early 1900s, prior to the emergence of many molecular models of anesthetic action in the 1960s.² The proposed mechanism by which lipophilicity impacts drug efficacy is through integration into the hydrophobic portion of the lipid bilayer, inducing a change in conformation that inhibits anesthesia sensitive ion channels.² General anesthetics are also proposed to have unique interactions with lipid rafts and cholesterol affinity, which alter the membrane’s lateral pressure profile.³

Limitations

Since Meyer and Overton’s findings, subsequent experiments have challenged the original results and cast doubt on the validity of the Meyer-Overton correlation. These limitations include:
- In an experiment on the isolated enzyme luciferase, naturally found in fireflies, the presence of anesthetic agents at concentrations that produce anesthetic effects in animals reduced enzyme activity by up to 50%.^4,5 The results indicate that an effect also exists between anesthetic compounds and proteins.⁴
- In a series of homologous anesthetics, as molecular size and lipophilicity increased, drug potency increased to a point as anticipated.⁴ However, once the size of the n-alkanes became large enough, the anesthetics lost their effects.⁶ This experiment supported the notion that a certain conformational binding arrangement applies a size restriction to anesthetic agents, termed a “Cut-Off effect.”⁴
- Multiple studies performed on larger and bulkier compounds found that they did not obey the Meyer-Overton rule. One experiment on polyhalogenated and perfluorinated compounds found that five compounds lacked anesthetic properties despite their ability to dissolve in lipids and tissues.^4,7
- Another experiment on aromatic compounds and cycloalkanes found that aromatic compounds produced less potent effects than n-alkanes and cycloalkanes despite greater molecular size and lipophilic properties.^4,8
- Several experimental results have shown varying drug potency with respect to stereospecificity. For instance, the (S+) enantiomer of isoflurane showed 53% greater potency on the standard minimum alveolar concentration assay compared to the (R-) enantiomer when tested on rat models.^4,9 A later experiment found that the (S+) enantiomer of isoflurane had about 40% greater potency than the (R-) enantiomer when suppressing the righting reflex in rats.^4,10 Because stereospecificity represents interaction with an optically active binding site on a protein, these results signal that there may exist interactions outside the lipid interactions suggested by the Meyer-Overton correlation.⁴

Graphical Representation

Figure 1. Modern interpretation of the Meyer-Overton correlation represented graphically. Source: NeuroImagem. Wikimedia Commons. CC0 1.0. https://commons.wikimedia.org/wiki/File:The_Meyer-Overton_Correlation_%28Final%29.png#filelinks

References

Hansch C. A quantitative approach to biochemical structure-activity relationships. Accounts of Chemical Research. 1969;2(8):232-9. Link
Hansen SB. Mechanisms of general anesthesia. Annual review of biochemistry. 2025;94(1):503-530. PubMed
Regen SL. Taking a deep dive into lipid-based mechanisms of general anesthetics. Biochemistry. 2023;62(7):1219-20. PubMed
Lugli AK, Yost CS, Kindler CH. Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anesthesia. Eur J Anaesthesiol. 2009;26(10):807-20. PubMed
Franks NP, Lieb WR. Do general anesthetics act by competitive binding to specific receptors? Nature. 1984;310(5978):599-601. PubMed
Raines DE, Miller KW. On the importance of volatile agents devoid of anesthetic action. Anesth Analg. 1994;79(6):1031-3. PubMed
Koblin DD, Chortkoff BS, Laster MJ, et al. Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis. Anesth Anal. 1994;79(6):1043-8. PubMed
Fang Z, Sonner J, Laster MJ, et al. Anesthetic and convulsant properties of aromatic compounds and cycloalkanes: implications for mechanisms of narcosis. Anesth Analg. 1996;83(5):1097-1104. PubMed
Lysko GS, Robinson JL, Casto R, et al. The stereospecific effects of isoflurane isomers in vivo. European Journal of Pharmacology. 1994;263(1-2):25-9. PubMed
Dickinson R, White I, Lieb WR, et al. Stereoselective loss of righting reflex in rats by isoflurane. Anesthesiology. 2000;93(3):837-43. PubMed

Other References

Gamboa J, Romano O. Inhaled anesthetic agents: Mechanism of action, uptake, and distribution. OA summary. 2023. Link

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