monoamine reuptake inhibitor

File:Kokain_-_Cocaine.svg

A monoamine reuptake inhibitor (MRI){{cite journal |vauthors=Axel AM, Mikkelsen JD, Hansen HH | title = Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat | journal = Neuropsychopharmacology | volume = 35 | issue = 7 | pages = 1464–76 |date=June 2010 | pmid = 20200509 | pmc = 3055463 | doi = 10.1038/npp.2010.16 }} is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

Uses

The majority of currently approved antidepressants act predominantly or exclusively as MRIs, including the selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and almost all of the tricyclic antidepressants (TCAs).{{cite book | author1 = Richard Finkel | author2 = Michelle Alexia Clark | author3 = Pamela C. Champe |author4=Luigi X. Cubeddu | title = Lippincott's Illustrated Reviews: Pharmacology | url = https://books.google.com/books?id=Q4hG2gRhy7oC&pg=PA141 | access-date = 12 May 2012 | date = 16 July 2008 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-7155-9 | page = 141}} Many psychostimulants used either in the treatment of {{abbrlink|ADHD|attention-deficit hyperactivity disorder}} or as appetite suppressants in the treatment of obesity also behave as MRIs, although notably amphetamine (and methamphetamine), which do act to some extent as monoamine reuptake inhibitors, exerts their effects primarily as releasing agents.{{Cite journal|last1=Walker|first1=Q. David|last2=Morris|first2=Sarah E.|last3=Arrant|first3=Andrew E.|last4=Nagel|first4=Jacqueline M.|last5=Parylak|first5=Sarah|last6=Zhou|first6=Guiying|last7=Caster|first7=Joseph M.|last8=Kuhn|first8=Cynthia M.|date=October 2010|title=Dopamine Uptake Inhibitors but Not Dopamine Releasers Induce Greater Increases in Motor Behavior and Extracellular Dopamine in Adolescent Rats Than in Adult Male Rats|journal=The Journal of Pharmacology and Experimental Therapeutics|volume=335|issue=1|pages=124–132|doi=10.1124/jpet.110.167320|issn=0022-3565|pmc=2957786|pmid=20605908}}{{cite book | author1 = Stefan Offermanns | author2 = Walter Rosenthal | title = Encyclopedia of Molecular Pharmacology | url = https://books.google.com/books?id=fGe6NDIGQpsC&pg=PA1039 | access-date = 12 May 2012 | year = 2008 | publisher = Springer | isbn = 978-3-540-38916-3 | page = 1039}} Additionally, psychostimulants acting as MRIs that affect dopamine such as cocaine and methylphenidate are often abused as recreational drugs.{{cite book | author1 = Pedro Ruiz | author2 = Eric C. Strain | title = Lowinson and Ruiz's Substance Abuse: A Comprehensive Textbook | url = https://books.google.com/books?id=w4ZUJAdleTsC&pg=PA55 | access-date = 12 May 2012 | date = 15 April 2011 | publisher = Lippincott Williams & Wilkins | isbn = 978-1-60547-277-5 | page = 55}} As a result, many of them have become controlled substances, which in turn has resulted in the clandestine synthesis of a vast array of designer drugs for the purpose of bypassing drug laws; a prime example of such is the mixed monoamine reuptake inhibitor and releasing agent mephedrone.{{cite journal |vauthors=Hadlock GC, Webb KM, McFadden LM, etal | title = 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 339 | issue = 2 | pages = 530–6 |date=November 2011 | pmid = 21810934 | doi = 10.1124/jpet.111.184119 | pmc = 3200001}}

Types of MRIs

There are a variety of different kinds of MRIs, of which include the following:

Specific for one monoamine transporter
Serotonin reuptake inhibitor (SRI)
Selective serotonin reuptake inhibitor (SSRI)
Norepinephrine reuptake inhibitor (NRI)
Selective norepinephrine reuptake inhibitor (sNRI)
Dopamine reuptake inhibitor (DRI)
Non-specific, binding to two or more monoamine transporters
Serotonin–norepinephrine reuptake inhibitor (SNRI)
Serotonin–dopamine reuptake inhibitor (SDRI)
Norepinephrine–dopamine reuptake inhibitor (NDRI)
Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)

Binding profiles

Compound	{{abbrlink\|SERT\|Serotonin transporter}}	{{abbrlink\|NET\|Norepinephrine transporter}}	{{abbrlink\|DAT\|Dopamine transporter}}	Type	Class
class="wikitable sortable sticky-header" style="text-align:left; font-size:small;" \|+ Binding profiles of {{abbr\|MRIs\|monoamine reuptake inhibitors}} at human {{abbr\|MATs\|monoamine transporters}}{{cite journal \| vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E \| title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters \| journal = Eur. J. Pharmacol. \| volume = 340 \| issue = 2–3 \| pages = 249–58 \| year = 1997 \| pmid = 9537821 \| doi = 10.1016/s0014-2999(97)01393-9\| url = https://www.academia.edu/download/45762636/s0014-2999_2897_2901393-920160518-31441-t07hp6.pdf}}{{dead link\|date=July 2022\|bot=medic}}{{cbignore\|bot=medic}}
3-Methylmethcathinone	4500	80	270	NDRI	Stimulant
Amfonelic acid	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}	207	DRI	Stimulant
Amineptine*{{cite journal \| vauthors = Ceci A, Garattini S, Gobbi M, Mennini T \| title = Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain \| journal = Br. J. Pharmacol. \| volume = 88 \| issue = 1 \| pages = 269–75 \| year = 1986 \| pmid = 3708219 \| pmc = 1917102 \| doi = 10.1111/j.1476-5381.1986.tb09495.x}}{{cite journal \|vauthors=Garattini S, Mennini T \|title=Pharmacology of amineptine: synthesis and updating \|journal=Clin Neuropharmacol \|volume=12 Suppl 2 \|pages=S13–8 \|year=1989 \|pmid=2698268 \|doi= 10.1097/00002826-198912002-00003\|s2cid=10947713 }}	>100,000 (rat)	10,000 (rat)	1,000–1,400 (rat)	DRI	Stimulant
Amitriptyline	4.30	35	3,250	SNRI	TCA
Amoxapine	58	16.0	4,310	SNRI	{{abbr\|TeCA\|Tetracyclic antidepressant}}
Amphetamine	>100,000	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}	{{abbr\|NDRA\|Norepinephrine–dopamine releasing agent}}	Stimulant
D-Amphetamine	>100,000	530	2,900	NDRA	Stimulant
L-Amphetamine	>100,000	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}	{{abbr\|NRA\|Norepinephrine releasing agent}}	Stimulant
Atomoxetine	77	5	1,451	NRI	Stimulant
Bupropion	9,100	52,000	520	NDRI	Stimulant
Butriptyline	1,360	5,100	3,940	N/A ({{abbr\|IA\|inactive}})	TCA
Chlorphenamine	15.2	1,440	1,060	SRI	Antihistamine
Citalopram	1.16	4,070	28,100	SRI	{{abbr\|SSRI\|Selective serotonin reuptake inhibitor}}
Escitalopram{{cite journal \| vauthors = Owens JM, Knight DL, Nemeroff CB \| title = [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine] \| language = fr \| journal = Encephale \| volume = 28 \| issue = 4 \| pages = 350–5 \| year = 2002 \| pmid = 12232544 }}	1.1	7,841	27,410	SRI	SSRI
Clomipramine	0.28	38	2,190	SNRI	TCA
Cocaethylene{{cite journal \| vauthors = Rothman RB, Baumann MH \| title = Monoamine transporters and psychostimulant drugs \| journal = Eur. J. Pharmacol. \| volume = 479 \| issue = 1–3 \| pages = 23–40 \| year = 2003 \| pmid = 14612135 \| doi = 10.1016/j.ejphar.2003.08.054}}	3,878	>10,000	555	SDRI	Stimulant
Cocaine	304	779	478	SNDRI	Stimulant
Cocaine{{cite web \| title=EMCDDA–Europol Joint Report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP) \| website=www.euda.europa.eu \| url=https://www.euda.europa.eu/publications/joint-reports/alpha-pvp_en \| access-date=2024-07-16}}	313±17 (IC₅₀)	292±34 (IC₅₀)	211±19 (IC₅₀)	SNDRI	Stimulant
Desipramine	17.6	0.83	3,190	SNRI	TCA
Desmethylcitalopram	3.6	1,820	18,300	SRI	SSRI
Desmethylsertraline	3.0	390	129	SRI	SSRI
Desmethylsibutramine{{cite journal \| vauthors = Nisoli E, Carruba MO \| title = An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action \| journal = Obes Rev \| volume = 1 \| issue = 2 \| pages = 127–39 \| year = 2000 \| pmid = 12119986 \| doi = 10.1046/j.1467-789x.2000.00020.x\| s2cid = 20553857 }}	15	20	49	SNDRI	SNRI
(R)-Desmethylsibutramine	44	4	12	SNDRI	SNRI
(S)-Desmethylsibutramine	9,200	870	180	SNDRI	SNRI
Desoxypipradrol{{cite journal\|author6-link=Bryan Roth \| vauthors = Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL \| title = Neurochemical profiles of some novel psychoactive substances \| journal = Eur. J. Pharmacol. \| volume = 700 \| issue = 1–3 \| pages = 147–51 \| year = 2013 \| pmid = 23261499 \| pmc = 3582025 \| doi = 10.1016/j.ejphar.2012.12.006 }}	53,700	550	50	NDRI	Stimulant
Desvenlafaxine*{{cite journal \| vauthors = Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH \| title = Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor \| journal = J. Pharmacol. Exp. Ther. \| volume = 318 \| issue = 2 \| pages = 657–65 \| year = 2006 \| pmid = 16675639 \| doi = 10.1124/jpet.106.103382 \| s2cid = 15063064 }}	47	531	{{abbr\|ND\|No data}}	SNRI	SNRI
Didesmethylsibutramine	20	15	45	SNDRI	SNRI
(R)-Didesmethylsibutramine	140	13	8.9	SNDRI	SNRI
(S)-Didesmethylsibutramine	4,300	62	12	SNDRI	SNRI
Diphenhydramine	3,800	960	2,200	N/A ({{abbr\|IA\|inactive}})	Antihistamine
Dosulepin (dothiepin)	8.6	46	5,310	SNRI	TCA
Doxepin	68	29.5	12,100	SNRI	TCA
Duloxetine*{{cite journal \| vauthors = Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ \| title = Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity \| journal = Biol. Psychiatry \| volume = 55 \| issue = 3 \| pages = 320–2 \| year = 2004 \| pmid = 14744476 \| doi = 10.1016/j.biopsych.2003.07.006 \| s2cid = 29448095 }}	3.7	20	439	SNRI	SNRI
Etoperidone	890	20,000	52,000	SRI	{{abbr\|SARI\|Serotonin antagonist and reuptake inhibitor}}
Eutylone{{cite journal \| vauthors = Glatfelter GC, Walther D, Evans-Brown M, Baumann MH \| title = Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation \| journal = ACS Chem Neurosci \| volume = 12 \| issue = 7 \| pages = 1172\| date = April 2021 \| pmid = 33689284 \| pmc = 9423000 \| doi = 10.1021/acschemneuro.0c00797 \| url =https://pubs.acs.org/doi/10.1021/acschemneuro.0c00797 }}	690	1,280	120	SNDRI	Stimulant
Femoxetine	11.0	760	2,050	SRI	SSRI
Fluoxetine	0.81	240	3,600	SRI	SSRI
Fluvoxamine	2.2	1,300	9,200	SRI	SSRI
GBR-12935	289	277	4.90	DRI	Stimulant
Hydroxybupropion{{cite journal \|last1=Damaj \|first1=MI \|last2=Carroll \|first2=FI \|last3=Eaton \|first3=JB \|last4=Navarro \|first4=HA \|last5=Blough \|first5=BE \|last6=Mirza \|first6=S \|last7=Lukas \|first7=RJ \|last8=Martin \|first8=BR \|title=Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors. \|journal=Molecular Pharmacology \|date=September 2004 \|volume=66 \|issue=3 \|pages=675–82 \|doi=10.1124/mol.104.001313 \|pmid=15322260 \|s2cid=1577336 }}	{{abbr\|ND\|No data}}	1.7 (IC₅₀)	>10 (IC₅₀)	NDRI	Stimulant
Imipramine	1.40	37	8,500	SNRI	TCA
Indatraline	3.10	12.6	1.90	SNDRI	Stimulant
Iprindole	1,620	1,262	6,530	N/A ({{abbr\|IA\|inactive}})	TCA
Lofepramine	70	5.4	18,000	SNRI	TCA
Maprotiline	5,800	11.1	1,000	NRI	TeCA
Mazindol	39	0.45	8.1	NDRI	Stimulant
{{abbrlink\|MDPV\|Methylenedioxypyrovalerone}}{{cite journal \| vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW \| title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products \| journal = Neuropsychopharmacology \| volume = 38 \| issue = 4 \| pages = 552–62 \| year = 2013 \| pmid = 23072836 \| pmc = 3572453 \| doi = 10.1038/npp.2012.204 }}	3,349	26	4.1	NDRI	Stimulant
Methamphetamine	>100,000	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}	NDRA	Stimulant
D-Methamphetamine	>100,000	660	2,800	NDRA	Stimulant
L-Methamphetamine	>100,000	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}	NRA	Stimulant
Methylphenidate	>10,000	788	121	NDRI	Stimulant
D-Methylphenidate	>10,000	206	161	NDRI	Stimulant
L-Methylphenidate	>6,700	>10,000	2,250	NDRI	Stimulant
Mianserin	4,000	71	9,400	NRI	TeCA
Milnacipran*	151	68	>100,000	SNRI	SNRI
Levomilnacipran*{{cite journal \| vauthors = Auclair AL, Martel JC, Assié MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortère R \| title = Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety \| journal = Neuropharmacology \| volume = 70 \| pages = 338–47 \| year = 2013 \| pmid = 23499664 \| doi = 10.1016/j.neuropharm.2013.02.024 \| doi-access = free }}	19.0	10.5	>100,000	SNRI	SNRI
Mirtazapine	>100,000	4,600	>100,000	N/A ({{abbr\|IA\|inactive}})	TeCA
Modafinil*{{cite journal \| vauthors = Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH \| title = Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil \| journal = J. Pharmacol. Exp. Ther. \| volume = 329 \| issue = 2 \| pages = 738–46 \| year = 2009 \| pmid = 19197004 \| pmc = 2672878 \| doi = 10.1124/jpet.108.146142 }}	>50,000	136,000	4,043	DRI	Stimulant
Nefazodone	200	360	360	SNDRI	SARI
Nefopam{{cite journal \| vauthors = Gregori-Puigjané E, Setola V, Hert J, Crews BA, Irwin JJ, Lounkine E, Marnett L, Roth BL, Shoichet BK \| title = Identifying mechanism-of-action targets for drugs and probes \| journal = Proc. Natl. Acad. Sci. U.S.A. \| volume = 109 \| issue = 28 \| pages = 11178–83 \| year = 2012 \| pmid = 22711801 \| pmc = 3396511 \| doi = 10.1073/pnas.1204524109 \| bibcode = 2012PNAS..10911178G \| doi-access = free }}	29	33	531	SNDRI	Analgesic
Nisoxetine	427	2.3	1,235	NRI	Stimulant
Nomifensine	1,010	15.6	56	NDRI	Stimulant
Norfluoxetine	1.47	1,426	420	SRI	SSRI
Nortriptyline	18	4.37	1,140	SNRI	TCA
Oxaprotiline	3,900	4.9	4,340	NRI	TeCA
Paroxetine	0.13	40	490	SRI	SSRI
Protriptyline	19.6	1.41	2,100	SNRI	TCA
Reboxetine{{cite journal \| vauthors = Bymaster FP, McNamara RK, Tran PV \| title = New approaches to developing antidepressants by enhancing monoaminergic neurotransmission \| journal = Expert Opin Investig Drugs \| volume = 12 \| issue = 4 \| pages = 531–43 \| year = 2003 \| pmid = 12665410 \| doi = 10.1517/13543784.12.4.531 \| s2cid = 20039451 }}	129	1.1	>10,000	NRI	Stimulant
Sertraline	0.29	420	25	SRI	SSRI
Sibutramine	298–2,800	350–5,451	943–1,200	SNDRI	SNRI
Trazodone	160	8,500	7,400	SRI	SARI
Trimipramine	149	2,450	3,780	SRI	TCA
Vanoxerine	73.2	79.2	4.3	DRI	Stimulant
Venlafaxine*	145	1,420	3,070	SNRI	SNRI
Vilazodone*{{cite journal \| vauthors = Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, Lucki I \| title = Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist \| journal = J. Pharmacol. Exp. Ther. \| volume = 302 \| issue = 3 \| pages = 1220–7 \| year = 2002 \| pmid = 12183683 \| doi = 10.1124/jpet.102.034280 \| s2cid = 12020750 }}	0.2	~60	{{abbr\|ND\|No data}}	SRI	{{abbr\|SMS\|Serotonin modulator and stimulator}}
Viloxazine	17,300	155	>100,000	NRI	Stimulant
Vortioxetine*{{cite journal \| vauthors = Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB \| title = Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder \| journal = J. Med. Chem. \| volume = 54 \| issue = 9 \| pages = 3206–21 \| year = 2011 \| pmid = 21486038 \| doi = 10.1021/jm101459g }}	5.4	890 (rat)	140 (rat)	SRI	SMS
Zimelidine	152	9,400	11,700	SRI	SSRI
class="sortbottom" \| colspan="7" \| Values are K_i (nM) or, in some cases, when denoted by an asterisk (*), {{abbrlink\|IC₅₀\|half-maximal inhibitory concentration}} (nM). The smaller the value, the more strongly the drug binds to or inhibits the transporter.

References

External links

{{Commons category-inline|Monoamine reuptake inhibitors}}