The effect of rigidity, shape, unsaturation, and length on the anesthetic potency of hydrocarbons.
We previously hypothesized that anesthesia results from an action on two sites separated by 5 A. The hypothesis relied on the finding that fluorinated alkanes having active anesthetic sites at each end of the molecule produce anesthesia as long as the total number of carbon atoms in their structure does not exceed five (i.e., approximately 5 A), and on the sustaining of the 5-A separation by the rigidity produced by fluorination. In this study, we tested an alternative hypothesis: that the site of action cannot accommodate a rigid compound, particularly a rectilinear compound, having more than five carbon atoms, and that rigidity itself might limit the anesthetic potency of larger compounds. We tested the anesthetic potency of 11 hydrocarbons in which rigidity was increased by unsaturation. In 72 rats exposed to such compounds, we found that unsaturation, rigidity, or both produced by unsaturation either did not change (double bonds) or increased (triple bonds) potency for a given number of carbon atoms. For example, we found that the rectilinear, rigid 2,4-trans-trans-hexadiene was no less potent (minimum alveolar anesthetic concentration [MAC] 0.042 +/- 0.002 atm; mean +/- SD) than the flexible 1,5-hexadiene (0.047 +/- 0.005 atm) or n-hexane (0.0467 +/- 0.0055 atm) and that 3-hexyne was more potent (MAC 0.0146 +/- 0.0014 atm) than n-hexane (MAC 0.0467 +/- 0.0055 atm). We conclude that the site of anesthetic action can accommodate straight rigid structures of up to six carbons in length.
Eger
E I
EI
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0464, USA. egere@anestesia.ucsf.edu
Laster
M J
MJ
D000769:Anesthesia, Inhalation; D000777:Anesthetics / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship
D000777:Anesthetics; D006845:Hydrocarbons, Fluorinated