Editing Clozapine (section)

===Pharmacodynamics===
{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}
{| class="wikitable floatright" style="font-size:small;"
|+ {{nowrap|Clozapine and [[norclozapine]] binding}}<ref name="PDSP" /><ref name="PDSP-2" />
|-
! Site
! {{abbr|CZP|Clozapine}} [[binding affinity|K<sub>i</sub>]] ({{abbr|nM|nanomolar}})
! {{abbrlink|NDMC|N-Desmethylclozapine}} [[binding affinity|K<sub>i</sub>]]
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 123.7 || 13.9
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 519 || 406.8
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 1,356 || 476.2
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 5.35 || 10.9
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] || 8.37 || 2.8
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 1.62 || 104.8
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || 7 || 85.2
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 37 || 137.6
|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] || 26.5 || 95.1
|-
| [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] || 6 || 117.7
|-
| [[Beta-1 adrenergic receptor|β<sub>1</sub>]] || 5,000 || 6,239
|-
| [[Beta-2 adrenergic receptor|β<sub>2</sub>]] || 1,650 || 4,725
|-
| [[Dopamine D1 receptor|D<sub>1</sub>]] || 266.25 || 14.3
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 157 || 101.4
|-
| [[Dopamine D3 receptor|D<sub>3</sub>]] || 269.08 || 193.5
|-
| [[Dopamine D4 receptor|D<sub>4</sub>]] || 26.36 || 63.94
|-
| [[Dopamine D5 receptor|D<sub>5</sub>]] || 255.33 || 283.6
|-
| [[Histamine H1 receptor|H<sub>1</sub>]] || 1.13 || 3.4
|-
| [[Histamine H2 receptor|H<sub>2</sub>]] || 153 || 345.1
|-
| [[Histamine H3 receptor|H<sub>3</sub>]] || 1 || 1
|-
| [[Histamine H4 receptor|H<sub>4</sub>]] || 6 || 1
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 6.17 || 67.6
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || 36.67 || 414.5
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] || 19.25 || 95.7
|-
| [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] || 15.33 || 169.9
|-
| [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]] || 15.5 || 35.4
|-
| colspan="3" style="width: 1px;" | The smaller the value, the more strongly the drug binds to the site. All data are for cloned human proteins.<ref name="PDSP">{{cite web|author1-link=Bryan Roth|title=PDSP K<sub>i</sub> Database|url=https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=clozapine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query|access-date=14 August 2017|work=Psychoactive Drug Screening Program (PDSP)|publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health|vauthors=Roth BL, Driscol J}}</ref><ref name="PDSP-2">{{cite web|title=PDSP K<sub>i</sub> Database|url=https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=norclozapine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query|access-date=14 August 2017|work=Psychoactive Drug Screening Program (PDSP)|publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health|vauthors=Roth BL, Driscol J}}</ref>
|}

Clozapine is classified as an [[atypical antipsychotic]] drug because it binds to [[serotonin]] as well as [[dopamine]] receptors.<ref name="Nahgre01">{{cite journal | vauthors = Naheed M, Green B | title = Focus on clozapine | journal = Current Medical Research and Opinion | volume = 17 | issue = 3 | pages = 223–229 | year = 2001 | pmid = 11900316 | doi = 10.1185/0300799039117069 | s2cid = 13021800 }}</ref> It acts as an antagonist at both receptors.

Clozapine is an inverse agonist at the 5-HT<sub>2A</sub> subtype of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.<ref>{{cite journal | title = CNS Receptor Partial Agonists: A New Approach to Drug Discovery | vauthors = Robinson DS | journal = Primary Psychiatry | year = 2007 | volume = 14 | issue = 8 | pages = 22–24 | url = http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1149 | url-status = dead | archive-url = https://web.archive.org/web/20120118091113/http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1149 | archive-date = 18 January 2012 }}</ref><ref>{{cite web|title=Clozapine {{!}} C18H19ClN4 | work = PubChem |url= https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2818| publisher = U.S. Library of Medicine |access-date=16 July 2017|url-status=live|archive-url=https://web.archive.org/web/20131224110428/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2818|archive-date=24 December 2013}}</ref>

A direct interaction of clozapine with the [[GABAB receptor|GABA<sub>B</sub> receptor]] has also been shown.<ref name="WUY">{{cite journal | vauthors = Wu Y, Blichowski M, Daskalakis ZJ, Wu Z, Liu CC, Cortez MA, Snead OC | title = Evidence that clozapine directly interacts on the GABAB receptor | journal = NeuroReport | volume = 22 | issue = 13 | pages = 637–641 | date = September 2011 | pmid = 21753741 | doi = 10.1097/WNR.0b013e328349739b | s2cid = 277293 }}</ref> GABA<sub>B</sub> receptor-deficient mice exhibit increased extracellular dopamine levels and altered [[Animal locomotion|locomotor]] behaviour equivalent to that in schizophrenia animal models.<ref name="VCM">{{cite journal | vauthors = Vacher CM, Gassmann M, Desrayaud S, Challet E, Bradaia A, Hoyer D, Waldmeier P, Kaupmann K, Pévet P, Bettler B | title = Hyperdopaminergia and altered locomotor activity in GABAB1-deficient mice | journal = Journal of Neurochemistry | volume = 97 | issue = 4 | pages = 979–991 | date = May 2006 | pmid = 16606363 | doi = 10.1111/j.1471-4159.2006.03806.x | s2cid = 19780444 }}</ref> GABA<sub>B</sub> receptor agonists and [[Allosteric regulation|positive allosteric modulators]] reduce the locomotor changes in these models.<ref name="WJM">{{cite journal | vauthors = Wierońska JM, Kusek M, Tokarski K, Wabno J, Froestl W, Pilc A | title = The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice | journal = British Journal of Pharmacology | volume = 163 | issue = 5 | pages = 1034–1047 | date = July 2011 | pmid = 21371011 | pmc = 3130949 | doi = 10.1111/j.1476-5381.2011.01301.x }}</ref>

Clozapine induces the release of glutamate and [[Serine|D-serine]], an agonist at the glycine site of the [[NMDA receptor]], from [[astrocyte]]s,<ref name="TAS">{{cite journal | vauthors = Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M | title = Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes | journal = British Journal of Pharmacology | volume = 165 | issue = 5 | pages = 1543–1555 | date = March 2012 | pmid = 21880034 | pmc = 3372736 | doi = 10.1111/j.1476-5381.2011.01638.x }}</ref> and [[SLC1A2|reduces the expression of astrocytic glutamate transporters]]. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor [[Gene expression|expression]] caused by NMDA receptor antagonists.<ref name="XID">{{cite journal | vauthors = Xi D, Li YC, Snyder MA, Gao RY, Adelman AE, Zhang W, Shumsky JS, Gao WJ | title = Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex | journal = Neuropsychopharmacology | volume = 36 | issue = 6 | pages = 1260–1274 | date = May 2011 | pmid = 21326193 | pmc = 3079418 | doi = 10.1038/npp.2011.12 }}</ref>