Chlorpromazine oligomer is a potentially active substance that inhibits humanD-amino acid oxidase, product of a susceptibility gene for schizophrenia

Abstract

D-Amino acid oxidase (DAO), a potential risk factor for schizophrenia, has been proposed to be involved in the decreased glutamatergic neurotransmission in schizophrenia. Here we show the inhibitory effect of an antipsychotic drug, chlorpromazine, on human DAO, which is consistent with previous reports using porcine DAO, although human DAO was inhibited to a lesser degree (K i ¼ 0.7 mM) than porcine DAO. Since chlorpromazine is known to induce phototoxic or photoallergic reactions and also to be transformed into various metabolites, we examined the effects of white light-irradiated chlorpromazine on the enzymatic activity. Analytical methods including high-resolution mass spectrometry revealed that irradiation triggered the oligomerization of chlorpromazine molecules. The oligomerized chlorpromazine showed a mixed type inhibition with inhibition constants of low micromolar range, indicative of enhanced inhibition. Taken together, these results suggest that oligomerized chlorpromazine could act as an active substance that might contribute to the therapeutic effects of this drug.

Effect of ligand binding on human D‐amino acid oxidase: Implications for the development of new drugs for schizophrenia treatment

“…The aliphatic phenothiazine CPZ is a dopamine D2 receptor antagonist that was introduced in the treatment of schizophrenia in the early 1950s; it also acts as a FAD-competitive inhibitor of hDAAO (K d ¼ 5 lM). 9,17 We here demonstrate that the different ligands affect the conformation and stability of the holoenzyme and apoprotein forms of the human flavoenzyme as well as the cellular concentration of hDAAO differently. We also provide evidence that these ligands do not alter the interaction between hDAAO and pLG72 and that affect the time course of cellular D-serine concentration similarly.…”

Inhibition of D-Amino Acid Oxidase Activity by Antipsychotic Drugs Evaluated by a Fluorometric Assay Using D-Kynurenine as Substrate

“…22 24) It has been reported that the mechanism by which CPZ can in-hibit DAAO activity was through the replacement of the cofactor FAD with CPZ. 23,24) Because most psychotropic drugs generally possess a planar tricyclic structure, other psychotropic drugs may have some DAAO-inhibitory activity. Therefore, we were interested in evaluating the inhibition of DAAO activity by other antipsychotic drugs prescribed to patients with psychiatric diseases.…”

Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro

“…Other drugs were purchased from Sigma Co. Ltd. (St. Louis, MO, USA), Tokyo Chemical Industries Co. Ltd. (Tokyo, Japan), and Wako Pure Chemical Industries Co. Ltd. (Osaka, Japan). Recombinant hDAO was prepared according to previously described methods (3,13,14), and the hDAO-inhibition assay was performed with D-KYN as a substrate, using methods similar to our previous paper (12).…”

“…These IC 50 values were comparable to that (2.41 ± 0.23 μM, n = 3) of MPC, a compound with established DAOinhibitory activity. The precise mechanism responsible for hDAO-inhibition is not clear, but chlorpromazine and risperidone have been reported to inhibit hDAO (13,18,19). The common features of the tested drugs were a heterocyclic moiety and a tertiary amino group.…”