Anesthetic potency of two novel synthetic polyhydric alkanols longer than the n-alkanol cutoff: evidence for a bilayer-mediated mechanism of anesthesia?
The polyhydroxyalkanes 1,6,11,16-hexadecanetetraol (1) and 2,7,12,17-octadecanetetraol (2) were synthesized utilizing the thiophene ring as a scaffold to affix the hydroxyalkyl chains by lithiation of the acidic alpha-hydrogens and subsequent desulfurization. Both compounds exhibited significant anesthetic potency, individually and in additivity studies with hexanol, using immobility in tadpoles as the phenotypic endpoint. These results, which contradict a protein-binding mechanism in which cutoff results from steric hindrance, are consistent with recent predictions of a membrane-mediated mechanism involving the lateral pressure profile.
Mohr
Justin T
JT
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA.
Gribble
Gordon W
GW
Lin
Susan S
SS
Eckenhoff
Roderic G
RG
Cantor
Robert S
RS
D018681:Anesthetics, General / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D005233:Fatty Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000441:Hexanols / Q000737:chemistry*; D007814:Larva / Q000187:drug effects; D008051:Lipid Bilayers / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D012995:Solubility; D014981:Xenopus
C501764:1,6,11,16-hexadecanetetraol; D018681:Anesthetics, General; D005233:Fatty Alcohols; D000441:Hexanols; D008051:Lipid Bilayers; C036260:1-hexanol