p-(4-Azipentyl)propofol: a potent photoreactive general anesthetic derivative of propofol.
We synthesized 2,6-diisopropyl-4-[3-(3-methyl-3H-diazirin-3-yl)propyl]phenol (p-(4-azipentyl)propofol), or p-4-AziC5-Pro, a novel photoactivable derivative of the general anesthetic propofol. p-4-AziC5-Pro has an anesthetic potency similar to that of propofol. Like propofol, the compound potentiates inhibitory GABA(A) receptor current responses and allosterically modulates binding to both agonist and benzodiazepine sites, assayed on heterologously expressed GABA(A) receptors. p-4-AziC5-Pro inhibits excitatory current responses of nACh receptors expressed in Xenopus oocytes and photoincorporates into native nACh receptor-enriched Torpedo membranes. Thus, p-4-AziC5-Pro is a functional general anesthetic that both modulates and photoincorporates into Cys-loop ligand-gated ion channels, making it an excellent candidate for use in identifying propofol binding sites.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, United States.
Deirdre S
DS
Stewart
Pavel Y
PY
Savechenkov
Zuzana
Z
Dostalova
David C
DC
Chiara
Rile
R
Ge
Douglas E
DE
Raines
Jonathan B
JB
Cohen
Stuart A
SA
Forman
Karol S
KS
Bruzik
Keith W
KW
Miller
D000494:Allosteric Regulation; D018681:Anesthetics, General / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D007814:Larva; D008024:Ligands; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry; D015742:Propofol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology; D012995:Solubility; D014101:Torpedo; D014982:Xenopus laevis
C570407:2,6-diisopropyl-4-(3-(3-methyl-3H-diazirin-3-yl)propyl)phenol; D018681:Anesthetics, General; D008024:Ligands; D018733:Nicotinic Antagonists; D019920:Photoaffinity Labels; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D003978:Diazomethane; D015742:Propofol