Editing Ketamine (section)

====Molecular targets====
{| class="wikitable floatright" style="font-size:small;"
|+ Ketamine and biological targets (with K<sub>i</sub> below 100 μM)

|-
! Site !! Value ([[Micromolar|μM]]) !! Type !! Action !! Species !! Ref
|-
| {{abbrlink|NMDA|N-Methyl-D-aspartate receptor}} || 0.25–0.66 || K<sub>i</sub> || Antagonist || Human || <ref name="pmid28829612">{{cite journal | vauthors = Morris PJ, Moaddel R, Zanos P, Moore CE, Gould TD, Zarate CA, Thomas CJ | title = Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites | journal = Organic Letters | volume = 19 | issue = 17 | pages = 4572–4575 | date = September 2017 | pmid = 28829612 | pmc = 5641405 | doi = 10.1021/acs.orglett.7b02177 }}</ref><ref name="pmid23527166">{{cite journal |author1-link= Bryan Roth | vauthors = Roth BL, Gibbons S, Arunotayanun W, Huang XP, Setola V, Treble R, Iversen L | title = The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e59334 | year = 2013 | pmid = 23527166 | pmc = 3602154 | doi = 10.1371/journal.pone.0059334 | bibcode = 2013PLoSO...859334R | doi-access = free | title-link = doi }}</ref>
|-
| {{abbrlink|MOR|μ-Opioid receptor}} || 42 || K<sub>i</sub> || Antagonist || Human || <ref name="pmid9915326">{{cite journal | vauthors = Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG | title = Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells | journal = Anesthesiology | volume = 90 | issue = 1 | pages = 174–82 | date = January 1999 | pmid = 9915326 | doi = 10.1097/00000542-199901000-00023 | doi-access = free | title-link = doi }}</ref>
|-
| {{abbrlink|MOR<sub>2</sub>|μ-Opioid receptor}} || 12.1
| K<sub>i</sub>
| Antagonist || Human || <ref name="pmid14530949">{{cite journal | vauthors = Hirota K, Sikand KS, Lambert DG | title = Interaction of ketamine with mu2 opioid receptors in SH-SY5Y human neuroblastoma cells | journal = Journal of Anesthesia | volume = 13 | issue = 2 | pages = 107–9 | year = 1999 | pmid = 14530949 | doi = 10.1007/s005400050035 | s2cid = 9322174 }}</ref>
|-
| {{abbrlink|KOR|κ-Opioid receptor}} || 28<br />25
| K<sub>i</sub><br />K<sub>i</sub>
| Antagonist<br />Agonist || Human ||<ref name="pmid9915326"/><br /><ref name="pmid20358363">{{cite journal |vauthors=Nemeth CL, Paine TA, Rittiner JE, Béguin C, Carroll FI, Roth BL, Cohen BM, Carlezon WA |title=Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats |journal=Psychopharmacology (Berl) |volume=210 |issue=2 |pages=263–74 |date=June 2010 |pmid=20358363 |pmc=2869248 |doi=10.1007/s00213-010-1834-7 }}</ref>
|-

| [[Sigma-2 receptor|σ<sub>2</sub>]] || 26 || K<sub>i</sub> || {{abbr|ND|No data}} || Rat || <ref name="pmid21911285">{{cite journal |vauthors=Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR |title=Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo |journal=Eur Neuropsychopharmacol |volume=22 |issue=4 |pages=308–17 |date=April 2012 |pmid=21911285 |doi=10.1016/j.euroneuro.2011.08.002 |s2cid=24494428 }}</ref>
|-
| [[D2 receptor|D<sub>2</sub>]] || 0.5<br/>&gt;10 || K<sub>i</sub><br />K<sub>i</sub> || Agonist<br />{{abbr|ND|No data}} || Human || <ref name="pmid12232776">{{cite journal | vauthors = Kapur S, Seeman P | title = NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia | journal = Molecular Psychiatry | volume = 7 | issue = 8 | pages = 837–44 | year = 2002 | pmid = 12232776 | doi = 10.1038/sj.mp.4001093 | doi-access = free | title-link = doi }}</ref><br /><ref name="pmid23527166" /><ref name="pmid27469513">{{cite journal | vauthors = Can A, Zanos P, Moaddel R, Kang HJ, Dossou KS, Wainer IW, Cheer JF, Frost DO, Huang XP, Gould TD | title = Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 359 | issue = 1 | pages = 159–70 | date = October 2016 | pmid = 27469513 | pmc = 5034706 | doi = 10.1124/jpet.116.235838 }}</ref><ref name="pmid16730695" />
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 45 || K<sub>i</sub> || {{abbr|ND|No data}} || Human || <ref name="pmid12456425">{{cite journal |vauthors=Hirota K, Hashimoto Y, Lambert DG |title=Interaction of intravenous anesthetics with recombinant human M1-M3 muscarinic receptors expressed in chinese hamster ovary cells |journal=Anesth Analg |volume=95 |issue=6 |pages=1607–10, table of contents |date=December 2002 |pmid=12456425 |doi=10.1097/00000539-200212000-00025 |s2cid=25643394 | doi-access = free | title-link = doi }}</ref>

|-
| {{abbrlink|α<sub>2</sub>β<sub>2</sub>|Nicotinic acetylcholine receptor}}|| 92 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635">{{cite journal |vauthors=Yamakura T, Chavez-Noriega LE, Harris RA |title=Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine |journal=Anesthesiology |volume=92 |issue=4 |pages=1144–53 |date=April 2000 |pmid=10754635 |doi=10.1097/00000542-200004000-00033 |s2cid=23651917 | doi-access = free | title-link = doi }}</ref>
|-
| {{abbrlink|α<sub>2</sub>β<sub>4</sub>|Nicotinic acetylcholine receptor}} || 29 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-

| [[alpha-3 beta-2 nicotinic receptor|α<sub>3</sub>β<sub>2</sub>]] || 50 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-

| [[alpha-3 beta-4 nicotinic receptor|α<sub>3</sub>β<sub>4</sub>]] || 9.5 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />

|-
| [[alpha-4 beta-2 nicotinic receptor|α<sub>4</sub>β<sub>2</sub>]] || 72 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />

|-
| [[alpha-4 beta-4 nicotinic receptor|α<sub>4</sub>β<sub>4</sub>]] || 18 || IC<sub>50</sub> || Antagonist || Human || <ref name="pmid10754635" />
|-
| [[Alpha-7 nicotinic receptor|α<sub>7</sub>]] || 3.1 ([[Hydroxynorketamine|HNK]]) || IC<sub>50</sub> || [[Negative allosteric modulation|NAM]]|| Rat || <ref name="pmid23183107">{{cite journal |vauthors=Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, Rosenberg A, Tran T, Xiao Y, Zarate CA, Wainer IW |title=Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors |journal=Eur J Pharmacol |volume=698 |issue=1–3 |pages=228–34 |date=January 2013 |pmid=23183107 |pmc=3534778 |doi=10.1016/j.ejphar.2012.11.023 }}</ref>

|-
| {{abbrlink|ERα|Estrogen receptor alpha}} || 0.34 || K<sub>i</sub>|| {{abbr|ND|No data}} || Human || <ref name="pmid29621538">{{cite journal | vauthors = Ho MF, Correia C, Ingle JN, Kaddurah-Daouk R, Wang L, Kaufmann SH, Weinshilboum RM | title = Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression | journal = Biochemical Pharmacology | volume = 152 | pages = 279–292 | date = June 2018 | pmid = 29621538 | pmc = 5960634 | doi = 10.1016/j.bcp.2018.03.032 }}</ref>

|-
| {{abbrlink|NET|Norepinephrine transporter}} || 82–291 || IC<sub>50</sub> || Inhibitor || Human ||<ref name="pmid9523822">{{cite journal |vauthors=Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, Tohyama M |title=Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells |journal=Anesthesiology |volume=88 |issue=3 |pages=768–74 |date=March 1998 |pmid=9523822 |doi=10.1097/00000542-199803000-00029 |s2cid=30159489 | doi-access = free | title-link = doi }}</ref><ref name="pmid18815045">{{cite journal |vauthors=Zhao Y, Sun L |title=Antidepressants modulate the in vitro inhibitory effects of propofol and ketamine on norepinephrine and serotonin transporter function |journal=J Clin Neurosci |volume=15 |issue=11 |pages=1264–9 |date=November 2008 |pmid=18815045 |pmc=2605271 |doi=10.1016/j.jocn.2007.11.007 }}</ref>
|-
| {{abbrlink|DAT|Dopamine transporter}} || 63 || K<sub>i</sub> || Inhibitor || Rat || <ref name="pmid9523822" />

|-
| {{abbrlink|HCN1|Hyperpolarization-activated cyclic nucleotide-gated channel 1}} || 8–16 || EC<sub>50</sub> || Inhibitor || Mouse || <ref name="pmid19158287">{{cite journal | vauthors = Chen X, Shu S, Bayliss DA | title = HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine | journal = The Journal of Neuroscience | volume = 29 | issue = 3 | pages = 600–9 | date = January 2009 | pmid = 19158287 | pmc = 2744993 | doi = 10.1523/JNEUROSCI.3481-08.2009 }}</ref>
|-
|[[TRPV1]]
|1-100
|K<sub>i</sub>
|Agonist
|Rat
|<ref>{{cite journal | vauthors = da Costa FL, Pinto MC, Santos DC, Carobin NV, de Jesus IC, Ferreira LA, Guatimosim S, Silva JF, Castro Junior CJ | title = Ketamine potentiates TRPV1 receptor signaling in the peripheral nociceptive pathways | journal = Biochemical Pharmacology | volume = 182 | pages = 114210 | date = December 2020 | pmid = 32882205 | doi = 10.1016/j.bcp.2020.114210 | s2cid = 221497233 }}</ref>
|- class="sortbottom"
| colspan="6" style="width: 1px;" | The smaller the value, the stronger the interaction with the site.
|}

Ketamine principally acts as a pore blocker of the [[NMDA receptor]], an [[ionotropic glutamate receptor]].<ref name="pmid28418641">{{cite journal | vauthors = Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ | title = Classics in Chemical Neuroscience: Ketamine | journal = ACS Chemical Neuroscience | volume = 8 | issue = 6 | pages = 1122–1134 | date = June 2017 | pmid = 28418641 | doi = 10.1021/acschemneuro.7b00074 }}</ref> The ''S''-(+) and ''R''-(–) [[stereoisomer]]s of ketamine bind to the dizocilpine site of the NMDA receptor with different [[Binding affinity|affinities]], the former showing approximately 3- to 4-fold greater affinity for the receptor than the latter. As a result, the ''S'' isomer is a more potent anesthetic and analgesic than its ''R'' counterpart.<ref name="pmid8942324">{{cite journal | vauthors = Hirota K, Lambert DG | title = Ketamine: its mechanism(s) of action and unusual clinical uses | journal = British Journal of Anaesthesia | volume = 77 | issue = 4 | pages = 441–4 | date = October 1996 | pmid = 8942324 | doi = 10.1093/bja/77.4.441 | df = dmy-all | doi-access = free | title-link = doi }}</ref>

Ketamine may interact with and inhibit the NMDAR via another [[allosteric site]] on the receptor.<ref name="Orser">{{cite journal | vauthors = Orser BA, Pennefather PS, MacDonald JF | title = Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors | journal = Anesthesiology | volume = 86 | issue = 4 | pages = 903–17 | date = April 1997 | pmid = 9105235 | doi = 10.1097/00000542-199704000-00021 | s2cid = 2164198 | doi-access = free | title-link = doi }}</ref>

With a couple of exceptions, ketamine actions at other receptors are far weaker than ketamine's antagonism of the NMDA receptor (see the activity table to the right).<ref name="MathewZarate2016" /><ref name="pmid26075331">{{cite journal | vauthors = Lodge D, Mercier MS | title = Ketamine and phencyclidine: the good, the bad, and the unexpected | journal = British Journal of Pharmacology | volume = 172 | issue = 17 | pages = 4254–76 | date = September 2015 | pmid = 26075331 | pmc = 4556466 | doi = 10.1111/bph.13222 }}</ref>

Although ketamine is a very weak ligand of the [[monoamine transporter]]s (K<sub>i</sub>&nbsp;> 60&nbsp;μM), it has been suggested that it may interact with [[allosteric site]]s on the monoamine transporters to produce [[monoamine reuptake inhibition]].<ref name="pmid23527166" /> However, no functional inhibition ([[IC50|IC<sub>50</sub>]]) of the human monoamine transporters has been observed with ketamine or its [[metabolite]]s at concentrations of up to 10,000&nbsp;nM.<ref name="pmid27469513" /><ref name="pmid28418641"/> Moreover, [[preclinical research|animal studies]] and at least three human [[case report]]s have found no interaction between ketamine and the [[monoamine oxidase inhibitor]] (MAOI) [[tranylcypromine]], which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as [[serotonin syndrome]] or [[hypertensive crisis]].<ref name="pmid28097909">{{cite journal | vauthors = Kraus C, Rabl U, Vanicek T, Carlberg L, Popovic A, Spies M, Bartova L, Gryglewski G, Papageorgiou K, Lanzenberger R, Willeit M, Winkler D, Rybakowski JK, Kasper S | title = Administration of ketamine for unipolar and bipolar depression | journal = International Journal of Psychiatry in Clinical Practice | volume = 21 | issue = 1 | pages = 2–12 | date = March 2017 | pmid = 28097909 | doi = 10.1080/13651501.2016.1254802 | s2cid = 35626369 }}</ref><ref name="pmid26302763">{{cite journal | vauthors = Bartova L, Vogl SE, Stamenkovic M, Praschak-Rieder N, Naderi-Heiden A, Kasper S, Willeit M | title = Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases | journal = European Neuropsychopharmacology | volume = 25 | issue = 11 | pages = 2183–4 | date = November 2015 | pmid = 26302763 | doi = 10.1016/j.euroneuro.2015.07.021 | s2cid = 39039021 }}</ref> Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans.<ref name="pmid28097909" /><ref name="pmid28418641" /><ref name="pmid27469513" /><ref name="pmid26302763" /> Ketamine has been found to increase [[Dopaminergic pathways|dopaminergic neurotransmission]] in the brain, but instead of being due to dopamine reuptake inhibition, this may be via [[upstream and downstream (transduction)|indirect/downstream]] mechanisms, namely through antagonism of the NMDA receptor.<ref name="pmid28418641" /><ref name="pmid27469513" />

Whether ketamine is an agonist of D<sub>2</sub> receptors is controversial. Early research by the [[Philip Seeman]] group found ketamine to be a D<sub>2</sub> partial agonist with a potency similar to that of its NMDA receptor antagonism.<ref name="pmid12232776" /><ref name="pmid18720422">{{cite journal | vauthors = Seeman P, Guan HC | title = Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia | journal = Synapse | volume = 62 | issue = 11 | pages = 819–28 | date = November 2008 | pmid = 18720422 | doi = 10.1002/syn.20561 | s2cid = 206519749 }}</ref><ref name="pmid19391150">{{cite journal | vauthors = Seeman P, Guan HC, Hirbec H | title = Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil | journal = Synapse | volume = 63 | issue = 8 | pages = 698–704 | date = August 2009 | pmid = 19391150 | doi = 10.1002/syn.20647 | s2cid = 17758902 }}</ref> However, later studies by different researchers found the affinity of ketamine of >10&nbsp;μM for the regular human and rat D<sub>2</sub> receptors,<ref name="pmid23527166" /><ref name="pmid27469513" /><ref name="pmid16730695">{{cite journal | vauthors = Jordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, Tadori Y, Kitagawa H, Kikuchi T | title = In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors | journal = European Journal of Pharmacology | volume = 540 | issue = 1–3 | pages = 53–6 | date = July 2006 | pmid = 16730695 | doi = 10.1016/j.ejphar.2006.04.026 }}</ref> Moreover, whereas D<sub>2</sub> receptor agonists such as [[bromocriptine]] can rapidly and powerfully suppress [[prolactin]] [[secretion]],<ref name="Springer2012">{{cite book|title=The Role of Brain Dopamine|url=https://books.google.com/books?id=yjHwCAAAQBAJ&pg=PA23|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73897-5|pages=23–}}</ref> subanesthetic doses of ketamine have not been found to do this in humans and in fact, have been found to dose-dependently ''increase'' prolactin levels.<ref name="pmid8122957">{{cite journal | vauthors = Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS | title = Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses | journal = Archives of General Psychiatry | volume = 51 | issue = 3 | pages = 199–214 | date = March 1994 | pmid = 8122957 | doi = 10.1001/archpsyc.1994.03950030035004 }}</ref><ref name="pmid11282259">{{cite journal | vauthors = Hergovich N, Singer E, Agneter E, Eichler HG, Graselli U, Simhandl C, Jilma B | title = Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial | journal = Neuropsychopharmacology | volume = 24 | issue = 5 | pages = 590–3 | date = May 2001 | pmid = 11282259 | doi = 10.1016/S0893-133X(00)00194-9 | doi-access = free | title-link = doi }}</ref> [[Medical imaging|Imaging]] studies have shown mixed results on inhibition of [[striatum|striatal]] [<sup>11</sup>C] [[raclopride]] binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect.<ref name="pmid17591653">{{cite journal | vauthors = Rabiner EA | title = Imaging of striatal dopamine release elicited with NMDA antagonists: is there anything there to be seen? | journal = Journal of Psychopharmacology | volume = 21 | issue = 3 | pages = 253–8 | date = May 2007 | pmid = 17591653 | doi = 10.1177/0269881107077767 | s2cid = 23776189 }}</ref> However, changes in [<sup>11</sup>C] raclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D<sub>2</sub> receptor.<ref name="pmid17591653" />