Synthesis and Properties of 3-(2-Hydroxyethyl)-3-<i>n</i>-pentyldiazirine, a Photoactivable General Anesthetic
作者:S. Shaukat Husain、Stuart A. Forman、Marek A. Kloczewiak、George H. Addona、Richard W. Olsen、Megan B. Pratt、Jonathan B. Cohen、Keith W. Miller
DOI:10.1021/jm9806300
日期:1999.8.1
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 mu M. 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 [H-3]muscimol binding to this receptor. In muscle nicotinic acetylcholine receptors (nAcChoR), it inhibited the response to acetylcholine with an IC50 of 33 mu M. 3-Diazirinyloctanol's pharmacological actions were comparable to those of octanol. 3-(2-Hydroxyethyl)-3-[4,5-H-3(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.