Editing Promethazine (section)

==Pharmacology==
Promethazine, a phenothiazine derivative, is structurally different from the [[neuroleptic]] phenothiazines, with similar but different effects.<ref name="pmid10965395">{{cite journal |vauthors=Strenkoski-Nix LC, Ermer J, DeCleene S, Cevallos W, Mayer PR | title = Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects | journal = American Journal of Health-System Pharmacy | volume = 57 | issue = 16 | pages = 1499–505 |date=August 2000 | pmid = 10965395 | doi = 10.1093/ajhp/57.16.1499| doi-access = free }}</ref> Despite structural differences, promethazine exhibits a strikingly similar binding profile to [[promazine]],<ref>{{Cite web |title=promazine {{!}} Ligand Activity Charts {{!}} IUPHAR/BPS Guide to PHARMACOLOGY |url=https://www.guidetopharmacology.org/GRAC/LigandActivityRangeVisForward?ligandId=7281 |access-date=18 May 2023 |website=www.guidetopharmacology.org |language=en}}</ref> another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.<ref>{{Cite book | vauthors = Möller HJ, Müller WE, Bandelow B |title=Neuroleptika – Pharmakologische Grundlagen, klinisches Wissen und therapeutisches Vorgehen |publisher=Wissenschaftliche Verlagsgesellschaft |year=2001 |isbn=978-3-8047-1773-2 |location=Stuttgart |language=German}}</ref> However, dosages used therapeutically, such as for sedation or sleep disorders, have no antipsychotic effect.<ref>{{Cite book| vauthors = Benkert O, Hippius H |date=1995 |title=Psychiatrische Pharmakotherapie  |language=en |doi=10.1007/978-3-642-79084-3|isbn=978-3-540-58149-9 }}</ref> It acts primarily as a strong [[receptor antagonist|antagonist]] of the [[H1 receptor|H<sub>1</sub> receptor]] ([[antihistamine]], ''K''<sub>i</sub> = 1.4 nM<ref>{{cite journal | vauthors = Hill SJ, Young M | title = Antagonism of central histamine H1 receptors by antipsychotic drugs | journal = European Journal of Pharmacology | volume = 52 | issue = 3–4 | pages = 397–399 | date = December 1978 | pmid = 32056 | doi = 10.1016/0014-2999(78)90297-2 }}</ref>) and a moderate [[muscarinic acetylcholine|mACh receptor]] antagonist ([[anticholinergic]]),<ref name="pmid10965395"/> and also has weak to moderate [[affinity (pharmacology)|affinity]] for the [[5-HT2A receptor|5-HT<sub>2A</sub>]],<ref name="pmid8584617">{{cite journal |vauthors=Fiorella D, Rabin RA, Winter JC | title = The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis | journal = Psychopharmacology | volume = 121 | issue = 3 | pages = 347–56 |date=October 1995 | pmid = 8584617 | doi = 10.1007/bf02246074| s2cid = 24420080 }}</ref> [[5-HT2C receptor|5-HT<sub>2C</sub>]],<ref name="pmid8584617" /> [[D2 receptor|D<sub>2</sub>]],<ref name="pmid2932631">{{cite journal | vauthors = Seeman P, Watanabe M, Grigoriadis D, etal | title = Dopamine D2 receptor binding sites for agonists. A tetrahedral model | journal = Molecular Pharmacology | volume = 28 | issue = 5 | pages = 391–9 | date = November 1985 | doi = 10.1016/S0026-895X(25)14176-X | pmid = 2932631 | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2932631 | access-date = 28 November 2011 | archive-date = 29 August 2021 | archive-url = https://web.archive.org/web/20210829012910/https://molpharm.aspetjournals.org/content/28/5/391.long | url-status = dead | url-access = subscription }}</ref><ref name="pmid847477">{{cite journal |vauthors=Burt DR, Creese I, Snyder SH | title = Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain | journal = Science | volume = 196 | issue = 4287 | pages = 326–8 |date=April 1977 | pmid = 847477 | doi = 10.1126/science.847477| bibcode = 1977Sci...196..326B }}</ref> and [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic receptor]]s,<ref name="JagadishPrasad2010">{{cite book | vauthors = Prasad JP | title = Conceptual Pharmacology | url = https://books.google.com/books?id=s0e_FlM8LKYC&pg=PA295 | access-date = 27 November 2011 | year = 2010 | publisher = Universities Press | isbn = 978-81-7371-679-9 | pages = 295, 303, 598}}</ref> where it acts as an antagonist at all sites, as well. New studies have shown that promethazine acts as a strong non-competitive selective [[NMDA receptor]] [[Receptor antagonist|antagonist]], with an EC50 of 20 μM;<ref name=":4" /> which might promote sedation in addition with the strong [[antihistamine]]rgic effects of the [[Histamine H1 receptor|H<sub>1</sub> receptor]], but also as a weaker [[analgesic]]. It does not, however, affect the [[AMPA receptor|AMPA]] receptors.<ref name=":4">{{cite journal | vauthors = Adolph O, Köster S, Georgieff M, Georgieff EM, Moulig W, Föhr KJ | title = Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug | journal = Neuropharmacology | volume = 63 | issue = 2 | pages = 280–291 | date = August 2012 | pmid = 22507664 | doi = 10.1016/j.neuropharm.2012.03.006 | s2cid = 35487146 }}</ref>

Another notable use of promethazine is as a [[local anesthetic]], by blockage of [[sodium channel]]s.<ref name="JagadishPrasad2010" />

{| class="wikitable sortable"
|+ Binding to receptors in nM [[Dissociation constant|(K<sub>i</sub>)]]
|-
! [[Receptor (biochemistry)|receptor]]
! [[Dissociation constant|K<sub>i</sub>]] (nM)
! ref
|-
| α1A-adrenoceptor (Rat)
| 32
| <ref name=":1">{{Cite web |title=promethazine {{!}} Ligand Activity Charts {{!}} IUPHAR/BPS Guide to PHARMACOLOGY |url=https://www.guidetopharmacology.org/GRAC/LigandActivityRangeVisForward?ligandId=7282 |access-date=18 May 2023 |website=www.guidetopharmacology.org |language=en}}</ref>
|-
| α1B-adrenoceptor (Rat)
| 21
| <ref name=":1" />
|-
| α1D-adrenoceptor (Human)
| 90
| <ref name=":1" />
|-
| α2A-adrenoceptor (Human)
| 256
| <ref name=":1" />
|-
| α2B-adrenoceptor (Human)
| 24
| <ref name=":1" />
|-
| α2C-adrenoceptor (Human)
| 353
| <ref name=":1" />
|-
| Calmodulin (Human)
| 60000
| <ref name="Bruno_2016">{{cite journal | vauthors = Bruno C, Cavalluzzi MM, Rusciano MR, Lovece A, Carrieri A, Pracella R, Giannuzzi G, Polimeno L, Viale M, Illario M, Franchini C, Lentini G  | title = The chemosensitizing agent lubeluzole binds calmodulin and inhibits Ca(2+)/calmodulin-dependent kinase II | journal = European Journal of Medicinal Chemistry | volume = 116 | issue =  | pages = 36–45 | date = June 2016 | pmid = 27043269 | doi = 10.1016/j.ejmech.2016.03.045 }}</ref><ref name=":1" /><ref name=":0">{{cite journal  |vauthors=Bolshan Y, Getlik M, Kuznetsova E, Wasney GA, Hajian T, Poda G, Nguyen KT, Wu H, Dombrovski L, Dong A, Senisterra G, Schapira M, Arrowsmith CH, Brown PJ, Al-Awar R, Vedadi M, Smil D |date=March 2013 |title=Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction |journal=ACS Medicinal Chemistry Letters |volume=4 |issue=3 |pages=353–357 |doi=10.1021/ml300467n |pmc=4027439 |pmid=24900672}}</ref>
|-
| Calmodulin (Bovine)
| 50000
| <ref name="Bruno_2016" /><ref name=":0" /><ref name=":1" />
|-
| Chloroquine resistance transporter (Plasmodium falciparum)
| 85000
|<ref name=":2">{{cite journal |vauthors=Deane KJ, Summers RL, Lehane AM, Martin RE, Barrow RA |date=May 2014 |title=Chlorpheniramine Analogues Reverse Chloroquine Resistance in Plasmodium falciparum by Inhibiting PfCRT |journal=ACS Medicinal Chemistry Letters |volume=5 |issue=5 |pages=576–581 |doi=10.1021/ml5000228 |pmc=4027738 |pmid=24900883}}</ref><ref name=":1" />
|-
| D1 receptor (Human)
| 1372
| <ref name=":1" />
|-
| D2 receptor (Human)
| 260
| <ref name=":1" />
|-
| D3 receptor (Human)
| 190
| <ref name=":1" />
|-
| H1 receptor (Human)
| 0.33<ref name=":1" />-1.4<ref name=":3">{{cite journal | vauthors = Nakai T, Kitamura N, Hashimoto T, Kajimoto Y, Nishino N, Mita T, Tanaka C | title = Decreased histamine H1 receptors in the frontal cortex of brains from patients with chronic schizophrenia | journal = Biological Psychiatry | volume = 30 | issue = 4 | pages = 349–356 | date = August 1991 | pmid = 1912125 | doi = 10.1016/0006-3223(91)90290-3 | s2cid = 9715772 }}</ref>
| <ref name=":3" /><ref name=":1" />
|-
| H2 receptor (Human)
| 1146
| <ref name=":1" />
|-
| M1 receptor (Human)
| 3.32
| <ref name=":1" />
|-
| M2 receptor (Human)
| 12
| <ref name=":1" />
|-
| M3 receptor (Human)
| 4.15
| <ref name=":1" />
|-
| M4 receptor (Human)
| 1.06
| <ref name=":1" />
|-
| M5 receptor (Human)
| 3.31
| <ref name=":1" />
|-
| NET (Human)
| 4203
| <ref name=":1" />
|-
| Prion protein (Human)
| 8000
| <ref name="pmid12904059">{{cite journal | vauthors = Vogtherr M, Grimme S, Elshorst B, Jacobs DM, Fiebig K, Griesinger C, Zahn R | title = Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 17 | pages = 3563–3564 | date = August 2003 | pmid = 12904059 | doi = 10.1021/jm034093h }}</ref><ref name=":1" />
|-
| 5-HT1A receptor (Rat)
| 1484
| <ref name=":1" />
|-
| 5-HT2A receptor (Human)
| 19
| <ref name=":1" />
|-
| 5-HT2B receptor (Human)
| 43
| <ref name=":1" />
|-
| 5-HT2C receptor (Human)
| 6.48
| <ref name=":1" />
|-
| 5-HT6 receptor (Human)
| 1128
| <ref name=":1" />
|-
| SERT (Serotonin transporter) (Human)
| 2130
| <ref name=":1" />
|-
| Sigma1 receptor (Human)
| 120
| <ref name=":1" />
|-
| OCT1 (Human)
| 35100
|<ref>{{cite journal  |vauthors=Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P |date=October 2008 |title=Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1 |journal=Journal of Medicinal Chemistry |volume=51 |issue=19 |pages=5932–5942 |doi=10.1021/jm8003152 |pmid=18788725}}</ref><ref name=":1" />
|}