BACKGROUND: Positive modulation of @entity1246 type A (GABAA) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including @entity1875 . The role for GABAA receptors as an essential site in the anesthetic actions of @entity1875 was recently challenged by a report that the @entity1875 analog @entity70322 ( @entity70323 ) potentiated and directly activated GABAA receptors, yet was devoid of sedative-anesthetic effects in @entity35 after intraperitoneal injection. Given the important implications of these findings for theories of anesthesia, the authors compared the effects of @entity70322 with those of @entity1875 using established in vivo and in vitro assays of both GABAA receptor-dependent and -independent anesthetic actions. METHODS: The effects of @entity1875 and @entity70322 were analyzed on heterologously expressed recombinant @entity1 GABAA alpha1beta2gamma2 receptors, evoked population spike amplitudes in @entity35 hippocampal slices, and @entity2227 release from @entity35 cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in @entity1238 tadpoles, in @entity19 after intraperitoneal injection, and in @entity35 after intravenous injection. RESULTS: Like @entity1875 , @entity70322 enhanced @entity1246 -induced currents in recombinant GABAA receptors, inhibited synaptic transmission in @entity35 hippocampal slices, and inhibited @entity1372 channel-mediated @entity2227 release from synaptosomes, but with reduced potency. After intraperitoneal injection, @entity70322 did not produce anesthesia in @entity19 , but it was not detected in serum or brain. However, @entity70322 did produce anesthesia in tadpoles (EC50 = 2.5 +/- 0.5 microM) and in @entity35 after intravenous injection (ED50 = 49 +/- 6.2 mg/kg). CONCLUSIONS: @entity1875 and @entity70322 produced similar actions on several previously identified cellular and molecular targets of general anesthetic action, and both compounds induced anesthesia in tadpoles and @entity35 . The failure of @entity70322 to induce anesthesia in rodents after intraperitoneal injection is attributed to a pharmacokinetic difference from @entity1875 rather than to major pharmacodynamic differences.

Anesthetic properties of XXXX : implications for mechanisms of anesthesia.

@entity1 :: ('9606', 'Species') :: ['human'] @entity2227 :: ('CHEBI:29987', 'Chemical') :: ['glutamate'] @entity1238 :: ('8355', 'Species') :: ['Xenopus laevis'] @entity1246 :: ('MESH:D005680', 'Chemical') :: ['gamma-aminobutyric acid', 'GABA'] @entity70323 :: ('MESH:C112421', 'Chemical') :: ['4-iodo-2,6-diisopropylphenol'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity1372 :: ('MESH:D012964', 'Chemical') :: ['sodium'] @entity1875 :: ('MESH:D015742', 'Chemical') :: ['propofol', 'Propofol'] @entity35 :: ('10116', 'Species') :: ['rat', 'rats'] @entity70322 :: ('MESH:C432026', 'Chemical') :: ['4-iodopropofol']
@entity70322 :: (MESH:C432026,Chemical) :: ['4-iodopropofol']
