Synthesis and Properties of 3-(2-Hydroxyethyl)-3-n-pentyldiazirine, a Photoactivable General Anesthetic

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 ED50 of 160 μM. Subanesthetic concentrations of 3-diazirinyloctanol enhanced GABA-induced currents in GABAA receptors, an effect that has been implicated in general anesthetic action. It also enhanced [3H]muscimol binding to this receptor. In muscle nicotinic acetylcholine receptors (nAcChoR), it inhibited the response to acetylcholine with an IC50 of 33 μM. 3-Diazirinyloctanol's pharmacological actions were comparable to those of octanol. 3-(2-Hydroxyethyl)-3-[4,5-3H2]-n-pentyldiazirine photoincorporated into Torpedo nAcChoR-rich membranes mainly in the α 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.