Actions of butyrophenones and other antipsychotic agents at NMDA receptors: relationship with clinical effects and structural considerations

Haloperidol inhibits NMDA receptors with higher affinity for NMDA receptors composed of NR1/2B compared with NR1/2A. To assess whether the clinical ef fects of haloperidol and other antipsychotic agents are mediated through th is site on NMDA receptors and to examine structure activity relationships a t this site, we examined the ability of a variety of drugs with neuroleptic actions to inhibit NMDA receptor function. Many antipsychotic agents inhib it I-125-MK 801 binding to the NMDA receptor with IC50 values in the microm olar range. The rank order of potency for inhibition of binding to adult ra t forebrain was trifluperidol (TFP) > clozapine = fluphenazine = reduced ha loperidol = spiperone = trifluoperazine = butaclamol much greater than pimo zide = risperidone = sulpiride. These findings match the molecular biologic al specificity of the agents, with trifluperidol having a marked preference for NR1/2B (epsilon 2) receptors, Mutations at epsilon 2E201, which alter the effects of haloperidol, also decrease the affinity of TFP but not other modulators, showing that the effect of TFP but not other modulators is med iated by this residue of the NMDA receptor. The present results demonstrate that while TFP acts on NMDA receptors in a manner similar to haloperidol, other antipsychotic agents do not share the specific pharmacological proper ties of this action, suggesting that their clinical mechanism is not mediat ed by this receptor. (C) 1999 Elsevier Science Ltd. All rights reserved.