Increasing D2 affinity results in the loss of clozapineʼs atypical antipsychotic action
Bibliographic record
Abstract
Typical antipsychotics (haloperidol) give rise to severe motor side-effects while atypical antipsychotics like clozapine do not. Action at several neurotransmitter receptors have been implicated. To identify the critical mechanisms involved we synthesized an 8-C1 isomer of clozapine which showed an equivalent affinity to clozapine on multiple receptors (5-HT1A, 5-HT2, D1, D4, M1) but differed in having a 10-fold higher affinity at the dopamine D2/3 receptor. When tested in a series of animal models indicative of the typical/atypical distinction (catalepsy, striatal gene-induction, prolactin elevation) isoclozapine lost atypical properties and behaved like a typical antipsychotic. Simultaneous in vivo receptor occupancy studies confirmed that alterations in D2 receptor occupancy were most closely related to loss of atypicality by clozapine's isomer isoclozapine. The implications for the design of future antipsychotics is discussed.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".