title: Synthesis and properties of 3-(2-hydroxyethyl)-3-n-pentyldiazirine, a photoactivable general anesthetic.
abstract: To overcome the difficulties of locating the molecular sites of general anesthetic action, we synthesized a novel photoactivable general anesthetic, 3-(2-hydroxyethyl)-3-n-pentyldiazirine (3-diazirinyloctanol), which anesthetized tadpoles with an ED(50) of 160 microM. Subanesthetic concentrations of 3-diazirinyloctanol enhanced GABA-induced currents in GABA(A) receptors, an effect that has been implicated in general anesthetic action. It also enhanced [(3)H]muscimol binding to this receptor. In muscle nicotinic acetylcholine receptors (nAcChoR), it inhibited the response to acetylcholine with an IC(50) of 33 microM. 3-Diazirinyloctanol's pharmacological actions were comparable to those of octanol. 3-(2-Hydroxyethyl)-3-[4,5-(3)H(2)]-n-pentyldiazirine photoincorporated into Torpedo nAcChoR-rich membranes mainly in the alpha subunit with 70% being in a proteolytic fragment containing the M4 transmembrane segment. Agonist enhanced the photolabeling 10-fold in a fragment containing the M1, M2, and M3 transmembrane segments. Thus, 3-diazirinyloctanol is a novel general anesthetic that acts on, and can be photoincorporated into, postsynaptic receptors.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Husain
authors.forename: S A
authors.initials: SA
authors.lastname: Forman
authors.forename: M A
authors.initials: MA
authors.lastname: Kloczewiak
authors.forename: G H
authors.initials: GH
authors.lastname: Addona
authors.forename: R W
authors.initials: RW
authors.lastname: Olsen
authors.forename: M B
authors.initials: MB
authors.lastname: Pratt
authors.forename: J B
authors.initials: JB
authors.lastname: Cohen
authors.forename: K W
authors.initials: KW
authors.lastname: Miller
mesh_terms: D000494:Allosteric Regulation; D018681:Anesthetics, General / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D000818:Animals; D001389:Azirines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000528:radiation effects; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism / Q000528:radiation effects; D002540:Cerebral Cortex / Q000378:metabolism; D004557:Electric Organ / Q000378:metabolism / Q000528:radiation effects / Q000648:ultrastructure; D006801:Humans; D066298:In Vitro Techniques; D007814:Larva; D008024:Ligands; D051379:Mice; D000442:Octanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000528:radiation effects; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011894:Rana pipiens; D011963:Receptors, GABA-A / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D014101:Torpedo; D014466:Ultraviolet Rays; D014981:Xenopus
chemical_list: C121210:3-(2-hydroxyethyl)-3-n-pentyldiazirine; D018681:Anesthetics, General; D001389:Azirines; D008024:Ligands; D000442:Octanols; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic