Neuropsychopharmacology : official publication of the American College of NeuropsychopharmacologyJun 3, 1998

M100907 and clozapine, but not haloperidol or raclopride, stop PCP from blocking NMDA responses in rat prefrontal cortex neurons

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

M100907 completely prevents or markedly reverses the phencyclidine (PCP)-induced blockade of N-methyl-D-aspartate (NMDA) responses in pyramidal neurons.

M100907 is a selective 5-HT2A receptor antagonist with significant effects on NMDA responses in the medial prefrontal cortex.
The stereoisomer M100009 does not exhibit the same activity as M100907.
Clozapine, an atypical antipsychotic, mimics the action of M100907, while typical antipsychotics like haloperidol do not.
Findings suggest that M100907 may serve as an antidote for PCP-induced psychosis, which resembles schizophrenia.
The ability of M100907 and clozapine to reverse NMDA receptor blockade could relate to their action on 5-HT2A receptors.

Simplified

In the present study, we demonstrate that, in a concentration-dependent manner, M100907 (formerly MDL 100907, a highly selective 5-HT2A receptor antagonist and a purported atypical antipsychotic drug [APD]), but not its much less active stereoisomer M100009, completely prevents or markedly reverses the phencyclidine (PCP)-induced blockade of N-methyl-D-aspartate (NMDA) responses in pyramidal neurons of the medial prefrontal cortex (mPFC). Furthermore, the atypical APD clozapine, but not the typical APD haloperidol or raclopride (a selective dopamine D2,3 receptor antagonist), mimicked the action of M100907, preventing the PCP-induced effect. These results suggest that M100907 might be an antidote for treating the PCP-induced psychotomimetic state that closely resembles schizophrenia; they could also account for the antipsychotic potential of M100907. Furthermore, our results suggest that the prototype (clozapine) and a candidate (M100907) atypical APDs might be effective in ameliorating schizophrenic symptoms including cognitive and neuropsychological deficits, which are induced in humans who abuse PCP. We hypothesize that the ability of M100907 and clozapine to prevent or reverse the PCP-induced blockade of the NMDA receptor channel is attributed to their 5-HT2A receptors antagonizing property. Therefore, with further systematic studies, the ability of compounds to prevent or reverse PCP's blockade of NMDA responses may prove to be an effective electrophysiological model for screening potential atypical APDs and predicting their therapeutic efficacy in cognitive deficits.

M100907 and clozapine, but not haloperidol or raclopride, stop PCP from blocking NMDA responses in rat prefrontal cortex neurons

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