Anesthetic and convulsant properties of aromatic compounds and cycloalkanes: implications for mechanisms of narcosis.
We examined the anesthetic and convulsant properties of 16 unfluorinated to completely fluorinated aromatic compounds, having six to nine carbon atoms (e.g., benzene to 1,3,5-tris(trifluoromethyl)benzene), and four cycloalkanes (cyclopentane to cyclooctane). Benzene, fluorobenzene, toluene, p-xylene, ethylbenzene, and cyclopentane caused excitation (twitching, jerking, and hyperactivity), and three aromatic compounds (perfluorotoluene, p-difluorotoluene and 1,3,5-tris(trifluoromethyl)benzene) and three cycloalkanes (cyclohexane, cycloheptane, and cyclooctane) produced convulsions. Cyclooctane and 1,3,5-tris(trifluoromethyl)benzene were nonanesthetics. Except for nonanesthetics and perfluorotoluene (too toxic to test for anesthetic potency), all compounds produced anesthesia or decreased the minimum alveolar anesthetic concentration of desflurane. Aromatic compounds were more potent and lipid-soluble than n-alkanes (data from previous report) and cycloalkanes. All three series increasingly disobeyed the Meyer-Overton hypothesis as molecular size increased. For a particular number of carbons (e.g., cyclohexane, n-hexane, and benzene), the deviation was cycloalkanes > or = normal alkanes > aromatic compounds. These results suggest that molecular shape (including "bulkiness") and size provide limited clues to the structure of the anesthetic site of action.
Fang
Z
Z
Department of Anesthesia, University of California, San Francisco 94143-0464, USA.
Sonner
J
J
Laster
M J
MJ
Ionescu
P
P
Kandel
L
L
Koblin
D D
DD
Eger
E I
EI
Halsey
M J
MJ
D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001554:Benzene / Q000494:pharmacology; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology*; D003292:Convulsants / Q000737:chemistry / Q000494:pharmacology*; D003508:Cycloheptanes / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D003516:Cycloparaffins / Q000737:chemistry / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology; D000077335:Desflurane; D005464:Fluorobenzenes / Q000494:pharmacology; D005466:Fluorocarbons / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced; D007530:Isoflurane / Q000031:analogs & derivatives / Q000494:pharmacology; D008055:Lipids; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014992:Xylenes / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D001555:Benzene Derivatives; D003292:Convulsants; D003508:Cycloheptanes; D003510:Cyclohexanes; D003516:Cycloparaffins; D003517:Cyclopentanes; D005464:Fluorobenzenes; D005466:Fluorocarbons; D008055:Lipids; D014992:Xylenes; D014050:Toluene; C059211:octafluorotoluene; C031286:4-xylene; D000077335:Desflurane; D007530:Isoflurane; D001554:Benzene; C004912:ethylbenzene