Polyhalogenated and Perfluorinated Compounds that Disobey the Meyer-Overton Hypothesis

Abstract

Fourteen polyhalogenated, completely halogenated (perhalogenated), or perfluorinated compounds were examined for their anesthetic effects in rats. Anesthetic potency or minimum alveolar anesthetic concentration (MAC) was quantified using response/nonresponse to electrical stimulation of the tail as the end-point. For compounds that produced excitable behavior, and/or did not produce anesthesia when given alone, we determined MAC by additivity studies with desflurane. Nine of 14 compounds had measurable MAC values with products of MAC x oil/gas partition coefficient ranging from 3.7 to 24.8 atm. Because these products exceed that for conventional inhaled anesthetics (1.8 atm), they demonstrate a deviation from the Meyer-Overton hypothesis. Five compounds (CF3CCIFCF3, CF3CCIFCCIFCF3, perfluorocyclobutane, 1,2-dichloroperfluorocyclobutane, and 1,2-dimethylperfluorocyclobutane) had no anesthetic effect when given alone, had excitatory effects when given alone, and tended to increase the MAC for desflurane. These five compounds had no anesthetic properties in spite of their abilities to dissolve in lipids and tissues, to penetrate into the central nervous system, and to be administered at high enough partial pressures so that they should have an anesthetic effect as predicted by the Meyer-Overton hypothesis. Such compounds will be useful in identifying and differentiating anesthetic sites and mechanisms of action. Any physiologic or biophysical/biochemical change produced by conventional anesthetics and deemed important for the anesthetic state should not be produced by nonanesthetics.

Enhancement of homomeric glycine receptor function by longchain alcohols and anaesthetics

“…... , 100- Figure 4a illustrates the effects on homomeric glycine receptor of two novel halogenated compounds: 1-chloro-1,2,2-trifluorocyclobutane (F3) and 1,2-dichlorohexafluorocyclobutane (F6). Both compounds have a high lipid solubility, and the Meyer-Overton rule predicts that both should act as anaesthetics in vivo (Meyer, 1899;Overton, 1901;Koblin et al, 1994). However, only F3 is an anaesthetic and a comparison of the effects of these compounds may be useful in testing candidate sites of anaesthetic action (Mihic et al, 1994).…”

“…To define better the actions of alcohols and anaesthetics on glycine receptors, we tested a series of n-alcohols, including long-chain alcohols that produce anaesthesia in vivo and show a 'cut-off' for effects on ligand-gated ion channels (Dildy-Mayfield et al, 1996). We also tested several clinically useful anaesthetics as well as two novel compounds which are structurally related, but only one of which produces anaesthesia (Koblin et al, 1994;Mihic et al, 1994). In order to examine the actions of different alcohols and anaesthetics in both al and a 2 glycine receptors, we used the Xenopus oocyte expression system.…”

The Size of the Unbranched Aliphatic Chain Determines the Immunomodulatory Potency of Short and Long Chain n-Alkanols

“…Also, a cutoff effect was evident when a homologous series of n-alkanols (or n-alkanes) was tested with increasing anesthetic activity being observed up to a discrete alcohol size after which it disappeared even though the larger ineffective molecules were highly lipophilic (16). Finally, compounds that possess high lipid solubility and fail to display anesthetic activity regardless of their size have been described in obvious discordance with the central tenet of the lipid theory (28).…”

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

“…The traditional dogma used to explain the mechanisms of action of volatile anesthetics has been that these compounds act 'non-specifically', perhaps by perturbing the properties of membrane lipids (reviewed by Franks and Lieb, 1994). However, research within the last several decades has demonstrated numerous inconsistencies between experimental observations and non-specific theories of general anesthesia (Franks and Lieb, 1994;Koblin et al, 1994;Krasowski and Harrison, 1999). A major problem with the non-specific theories is that some chemical compounds predicted to be anesthetics based upon their lipophilicity do not in fact produce anesthesia (Koblin et al, 1994).…”

“…However, research within the last several decades has demonstrated numerous inconsistencies between experimental observations and non-specific theories of general anesthesia (Franks and Lieb, 1994;Koblin et al, 1994;Krasowski and Harrison, 1999). A major problem with the non-specific theories is that some chemical compounds predicted to be anesthetics based upon their lipophilicity do not in fact produce anesthesia (Koblin et al, 1994). These compounds, originally called 'nonanesthetics', are now more properly referred to as 'nonimmobilizers'.…”