R‐ and S‐ mTFD‐MPPB, an Anesthetic and a Convulsant, Have Opposing Effect on γ‐Aminobutyric acid (GABA) type A Receptors

Abstract

The R‐enantiomer of 1‐methyl‐5‐phenyl‐5‐propyl barbituric acid (MPPB) is an anesthetic whereas the S is a convulsant. We synthesized its trifluoromethyl derivative (mTFD‐MPPB), a novel photoactivable barbiturate. R‐ and S‐mTFD‐MPPB caused loss of righting reflex in tadpoles (EC50 28 μM & 40 μM respectively) but the S‐enantiomer caused excitability. Next we used whole‐cell patch clamp electrophysiology with fast solution exchange (<1 millisecond) on recombinant human α1β3γ2 GABAA receptors expressed in HEK cells and found both enantiomers acted on GABAA currents more potently than MPPB. Currents elicited by low GABA concentration (10 μM) were increased 5‐fold by RmTFD‐MPPB (46μM), but decreased by ~70% by S‐mTFD‐MPPB (46μM). Enhancement was never observed with S‐mTFD‐MPPB at any concentration tested. At high GABA concentration (10 mM), both mTFD‐MPPB enantiomers (46μM) inhibited currents by ~30%. The enantiomers’ actions at low GABA are more consistent with their pharmacology, suggesting that the physiological locus of action is a GABAAR that functions at low GABA occupancy or where GABA is a partial agonist. This might include extrasynaptic receptors such as those containing δ‐subunits. Supported by GM58448.