The convulsant and anesthetic properties of cis-trans isomers of 1,2-dichlorohexafluorocyclobutane and 1,2-dichloroethylene.
The differences in potencies of optical isomers of anesthetics support the hypothesis that anesthetics act by specific receptor interactions. Diastereoisomerism and geometrical isomerism offer further tests of this hypothesis but have not been explored. They are the subject of this report. We quantified the nonimmobilizing and convulsant properties of the cis and trans diastereomers of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane). Although the lipophilicity of the diastereomers predicts complete anesthesia at the partial pressures applied, neither diastereomer had anesthetic activity alone, and the cis form may have a small (10%) capacity to antagonize anesthesia, as defined by additive effects on the MAC (the minimum alveolar concentration required to suppress movement to a noxious stimulus in 50% of rats) of desflurane. Both diastereomers produced convulsions, the cis form being nearly twice as potent as the trans form: convulsant 50% effective dose (mean +/- SD) was 0.039 +/- 0.009 atmospheres (atm) for the purified cis and 0.064 +/- 0.009 atm for the purified trans isomer. The MAC value for cis-1,2-dichloroethylene equaled 0.0071 +/- 0.0006 atm, and MAC for trans-1,2-dichloroethylene equaled 0.0183 +/- 0.0031 atm. In qualitative accord with the Meyer-Overton hypothesis, the greater cis potency was associated with a greater lipophilicity. However, the product of MAC x solubility differed between the cis and trans isomers by 40%-50%. We conclude that neither the cis nor trans isomers of 2N have anesthetic properties, but isomerism does influence 2N's convulsant properties and the anesthetic properties of dichloroethylene. These isomeric effects may be as useful in defining receptor-anesthetic interactions as those found with optical isomers.


CONCLUSIONS
Cis-trans isomerism can influence the convulsant properties of the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) and the anesthetic properties of dichloroethylene. Such isomeric effects may be as useful as those found with optical isomers in defining receptor-anesthetic interactions.
Eger
E I
EI
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0464, USA. egere@anesthesia.ucsf.edu
Halsey
M J
MJ
Koblin
D D
DD
Laster
M J
MJ
Ionescu
P
P
Königsberger
K
K
Fan
R
R
Nguyen
B V
BV
Hudlicky
T
T
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D017402:Chlorofluorocarbons / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D003503:Cyclobutanes / Q000494:pharmacology*; D000077335:Desflurane; D004000:Dichloroethylenes / Q000494:pharmacology*; D004558:Electric Stimulation; D007530:Isoflurane / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D018685:Anesthetics, Inhalation; D017402:Chlorofluorocarbons; D003292:Convulsants; D003503:Cyclobutanes; D004000:Dichloroethylenes; C090640:1,2-dichloro-1,2,3,3,4,4-hexafluorocyclobutane; D000077335:Desflurane; D007530:Isoflurane; C035384:1,2-dichloroethylene