PT - JOURNAL ARTICLE AU - O. A. SHEMISA AU - L. A. FAHIEN TI - Modifications of Glutamate Dehydrogenase by Various Drugs Which Affect Behavior DP - 1971 Jan 01 TA - Molecular Pharmacology PG - 8--25 VI - 7 IP - 1 4099 - http://molpharm.aspetjournals.org/content/7/1/8.short 4100 - http://molpharm.aspetjournals.org/content/7/1/8.full SO - Mol Pharmacol1971 Jan 01; 7 AB - The studies presently reported are consistent with the concept that chlorpromazine, certain isosteres of phenothiazine, and haloperidol (all drugs known to affect behavior) are inhibitors of glutamate dehydrogenase. These drugs apparently are bound to a site on the enzyme distinctly different from the active or purine nucleotide-binding sites. A lysine group on the enzyme molecule which is quite reactive with pyridoxal phosphate and is essential for full enzyme activity and allostery does not seem to be part of the drug-binding site. However, after this lysine group has reacted with pyridoxal phosphate, chlorpromazine will not inhibit the enzyme. Since binding of these drugs alters the absorption spectrum, fluorescence, and sedimentation coefficient of the enzyme, it is believed that inhibition by these drugs is secondary to an induced change in the conformation of the enzyme. In general the drugs are more inhibitory if the enzyme is already in a rather inactive conformation, i.e., if high concentrations of DPNH or GTP are present, and much less inhibitory if the enzyme is in an activated conformation, i.e., in the presence of high concentrations of ADP or DPN. Therefore the conformational changes produced by the drugs seem to be enhanced in the inactivated enzyme and retarded in the activated enzyme. In the presence of TPNH the drugs have little effect unless GTP is present. The drugs are extremely inhibitory in the presence of DPNH only if the concentration of DPNH is sufficiently high to produce substrate inhibition. ATP does not markedly alter the inhibitory action of the drugs with either coenzyme, and none of the drugs is a potent inhibitor in the presence of ADP or DPN. Therefore these agents would be most effective as inhibitors of ammonia incorporation if the DPNH:DPN and ATP:ADP ratios are high or if the concentrations of both TPNH and GTP are high. A detailed structure-activity study of the effects of many isosteres of promazine on glutamate dehydrogenase was performed, and the essential parts of the drug molecule necessary for binding to the drug site were characterized. The effects of these isosteres on glutamate dehydrogenase correlate closely with their antipsychotic activity in vivo.