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{{Short description|Class of pharmaceutical drugs}}
{{Distinguish|Tetracycline}}
{{Distinguish|Tetracycline|Tricyclic antidepressant}}
{{Refimprove|date=November 2013}}
] of tetracyclic antidepressant ]. Note its '''four fused''' ].]] ] of the TeCA ]. Notice its four ] fused together.]]


'''Tetracyclic antidepressants''' ('''TeCAs''') are a class of ]s that were first introduced in the 1970s. They are named after their ], which contains four ], and are closely related to the ]s (TCAs), which contain three rings of atoms. '''Tetracyclic antidepressants''' ('''TeCAs''') are a class of ]s that were first introduced in the 1970s. They are named after their ] ], containing four ], and are closely related to the ]s (TCAs), which contain three rings of atoms.


== List of TeCAs == ==List of TeCAs==
The TeCAs include:
* Marketed
** ] (Deprilept, Ludiomil, Psymion)
** ] (Bolvidon, Norval, Tolvon)
** ] (Remeron, Avanza, Zispin)
** ] (Pirazidol) — a tetracyclic ] (RIMA) used in Russia
** ] (Tecipul)
* Not marketed
** ] (CGS-7525A)
** ] (ORG-50,081)
** ] — a tetracyclic RIMA investigated as an antidepressant
** ] (C 49-802 BDA)
* Doubtful classification — the following agents contain four rings not fused together
** ] (Asendin) — widely classified as a secondary amine tricyclic antidepressant
** ] (WY-23,409)
** ] (BI-27,062)
** ] (Loxapac, Loxitane, Adasuve) — a tricyclic ] with antidepressant properties; produces amoxapine as an ]
** ] (Mazanor, Sanorex)


== Pharmacology == ===Marketed===
* ] (Ludiomil) – can also be classified as a TCA and grouped with the ]s
* ] (Tolvon)
* ] (Remeron)
* ] (Tecipul)


Drugs that contain four rings not all fused together but are sometimes still classified as TeCAs include:
=== Binding profiles ===
The ] (K<sub>d</sub> (nM)) of a selection of TeCAs have been compared below at an assortment of ]s:<ref name=Goodman>{{cite book|last=Brunton|first=Laurence|title=Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th Edition|year=2011|publisher=McGraw-Hill|location=China|isbn=978-0-07-162442-8|pages=406–410}}</ref><ref name="pmid9537821">{{cite journal |vauthors=Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–258 |date=December 1997 | pmid = 9537821 | doi = 10.1016/S0014-2999(97)01393-9| url = http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(97)01393-9}}</ref><ref name="pmid3816971">{{cite journal |vauthors=Wander TJ, Nelson A, Okazaki H, Richelson E | title = Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro | journal = European Journal of Pharmacology | volume = 132 | issue = 2–3 | pages = 115–121 |date=December 1986 | pmid = 3816971 | doi = 10.1016/0014-2999(86)90596-0| url = }}</ref><ref name="pmid6086881">{{cite journal |vauthors=Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 230 | issue = 1 | pages = 94–102 |date=July 1984 | pmid = 6086881 | doi = | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6086881}}</ref><ref name="pmid10193665">{{cite journal |vauthors=Tatsumi M, Jansen K, Blakely RD, Richelson E | title = Pharmacological profile of neuroleptics at human monoamine transporters | journal = European Journal of Pharmacology | volume = 368 | issue = 2–3 | pages = 277–283 |date=March 1999 | pmid = 10193665 | doi = 10.1016/S0014-2999(99)00005-9| url = }}</ref><ref name="pmid2891550">{{cite journal |vauthors=Wander TJ, Nelson A, Okazaki H, Richelson E | title = Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro | journal = European Journal of Pharmacology | volume = 143 | issue = 2 | pages = 279–282 |date=November 1987 | pmid = 2891550 | doi = 10.1016/0014-2999(87)90544-9| url = http://linkinghub.elsevier.com/retrieve/pii/0014-2999(87)90544-9}}</ref><ref name="pmid6149136">{{cite journal |vauthors=Richelson E, Nelson A | title = Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro | journal = European Journal of Pharmacology | volume = 103 | issue = 3–4 | pages = 197–204 |date=August 1984 | pmid = 6149136 | doi = 10.1016/0014-2999(84)90478-3| url = }}</ref><ref name="pmid15771415">{{cite journal |vauthors=Fernández J, Alonso JM, Andrés JI, etal | title = Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 6 | pages = 1709–12 |date=March 2005 | pmid = 15771415 | doi = 10.1021/jm049632c}}</ref><ref name="pmid3419539">{{cite journal |vauthors=de Boer TH, Maura G, Raiteri M, de Vos CJ, Wieringa J, Pinder RM | title = Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers | journal = Neuropharmacology | volume = 27 | issue = 4 | pages = 399–408 |date=April 1988 | pmid = 3419539 | doi = 10.1016/0028-3908(88)90149-9| url = }}</ref>


* ] (Asendin) – often classified as a TCA and grouped with the secondary amines
{| class="wikitable" class="sortable wikitable"
* ] (Seroquel) - an ] sometimes used as an adjunct antidepressant
| '''Compound''' || ''']''' || ''']''' || ''']''' || ''']''' || ''']''' || ''']''' || ''']''' || ''']''' || ''']''' || ''']'''

|-
====Miscellaneous====
| ] || 58 || 16.0 || 4,310 || 220 || 0.6 || 50 || 2,600 || 160 || 25 || 1,000
* ] (Tacitin) – a tetracyclic compound and is closely related to maprotiline, with the two compounds differing only in the length of their ], but benzoctamine is not used as an antidepressant and is instead used as an ]
|-
* ] (Adasuve, Loxitane) – a ] that produces amoxapine as a major ] and is said to have antidepressant effects, but it is not usually regarded as a TeCA
| ] || 2,400 || 380 || 9,000 || 2,900 || 1.7 || 28 || 2,400 || 70 || 4.9 || 450

|-
Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:
| ] || 5,800 || 11.1 || 1,000 || 12,000 || 120 || 91 || 9,400 || 350 || 2.0 || 560

|-
* ] (Mazanor, Sanorex) – a ] used as an ] and with potential antidepressant effects, but not classified as a TeCA
| ] || 4,000 || 101 || 9,400 || 190 || 4.3 || 74 || 4.3 || 2,197 || 1.7 || 820

|-
===Never marketed===
| ] || >100,000 || 1,640 || >100,000 || ? || 69 || 500 || 19 || >5,454 || 0.1 || 670
* ] (CGS-7525A) – a close ] of mirtazapine
|-
* ] (ORG-50,081) – the (''S'')-(+) ] of mirtazapine
| ] || 3,900 || 4.9 || 4,340 || 67,000 || 2,400 || 620 || 42,000 || ? || 21 || 2,900
* ] (C 49-802 BDA) – a close analogue of maprotiline

Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:

* ] (WY-23,409) – a close analogue of mazindol

==Pharmacology==
{{See also|Pharmacology of antidepressants}}

TeCAs have diverse ] and differ from TCAs in a number of ways. With the exception of amoxapine, TeCAs do not ] the ] of ]{{Citation needed|date=July 2020}}. However, aside from mirtazapine, they do inhibit the reuptake of ]{{Citation needed|date=July 2020}}. TeCAs block the ] ]s similarly to TCAs. Besides mirtazapine, they also block the ]{{Citation needed|date=July 2020}}. Conversely, whereas TCAs have relatively low ] for the ], mianserin and mirtazapine potently antagonize this receptor, and this action is thought to be involved in their antidepressant effects{{Citation needed|date=July 2020}}. TeCAs block the ] ] similarly to the TCAs, but tend to be even stronger ]s than TCAs{{Citation needed|date=July 2020}}. On the other hand, in contrast to almost all TCAs, TeCAs have only low affinity for the ]s, and for this reason, are associated with few or no ] ]s{{Citation needed|date=July 2020}}. Mianserin and mirtazapine are far less ] than TCAs in ].<ref>{{Cite journal|last=Shaw|first=W. L.|date=1980-01-01|title=The comparative safety of mianserin in overdose|url=https://doi.org/10.1185/03007998009114803|journal=Current Medical Research and Opinion|volume=6|issue=sup7|pages=44–51|doi=10.1185/03007998009114803|issn=0300-7995}}</ref><ref>{{Cite journal|last1=Waring|first1=W. Stephen|last2=Good|first2=Alison M.|last3=Bateman|first3=D. Nicholas|date=2007-01-01|title=Lack of significant toxicity after mirtazapine overdose: A five-year review of cases admitted to a regional toxicology unit|url=https://doi.org/10.1080/15563650601005837|journal=Clinical Toxicology|volume=45|issue=1|pages=45–50|doi=10.1080/15563650601005837|pmid=17357381 |s2cid=28546654 |issn=1556-3650}}</ref>

===Binding profiles===
{{See also|Tricyclic antidepressant#Binding profiles}}

The binding profiles of various TeCAs in terms of their ] ({{abbr|K<sub>i</sub>|inhibitory constant}}, {{abbr|nM|nanomolar}}) for various ]s and ]s are as follows:<ref name="PDSP">{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | author1 = Roth, BL | author2 = Driscol, J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/kidb.php}}</ref>

{| class="wikitable sortable" style="font-size: 80%; text-align: center;"
|+
! Compound !! {{abbrlink|SERT|Serotonin transporter}} !! {{abbrlink|NET|Norepinephrine transporter}} !! {{abbrlink|DAT|Dopamine transporter}} !! ] !! ] !! ] !! ] !! ] !! ] !! ] !! ] !! ] !! ] !!] !! ] !! {{abbrlink|mACh|Muscarinic acetylcholine receptor}}
|-
| ] || 58 || 16 || 4,310 || {{abbr|ND|No data}} || 0.5 || {{abbr|ND|No data}} || 2.0 || {{abbr|ND|No data}} || 6.0–50 || 41 || 50 || 2,600 || 3.6–160 || 7.9–25 || {{abbr|ND|No data}} || 1,000
|-
| ] || 5,800 || 11–12 || 1,000 || {{abbr|ND|No data}} || 51 || {{abbr|ND|No data}} || 122 || ND ||{{abbr|ND|No data}} || 50 || 90 || 9,400 || 350–665 || 0.79–2.0 || 776 || 570
|-
| ] || 4,000 || 71 || 9,400 || 400–2,600 || 1.6–20 || 1.6–55 || 0.63–6.5 || 5.8–300 || 55–81 || 48–56 || 34 || 3.8–73 || ≥2,100 || 0.30–1.7 || 437 || 820
|-
| ] || >10,000 || ≥4,600 || >10,000 || ≥3,330 || 6.3–69 || 200 || 8.9–39 || 7.9 || {{abbr|ND|No data}} || 265 || 316–1,815 || 18–88 || >5,454 || 0.14–1.6 || >10,000 || 670
|-
| ] || >10,000 || 220 || >10,000 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || 24 || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|- class="sortbottom"
| colspan="17" | Values are {{abbr|K<sub>i</sub>|inhibitory constant}} ({{abbr|nM|nanomolar}}). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.
|} |}


The selected ligands act as ] (or ]s depending on the site in question) at all ] listed and as ] of all ] listed. The TeCAs act as ] or ]s of the receptors and as ]s of the transporters.


==See also== ==See also==
* ]
*]
*] * ]


== References == ==References==
{{Reflist|2}} {{Reflist|2}}


{{Antidepressants}} {{Antidepressants}}
{{Navboxes
{{Cholinergics}}
| title = ]
{{Histaminergics}}
| titlestyle = background:#ccccff
{{Serotonergics}}
| list1 =
{{Tricyclics}}
{{Adrenergic receptor modulators}}
{{Dopamine receptor modulators}}
{{Histamine receptor modulators}}
{{Monoamine reuptake inhibitors}}
{{Muscarinic acetylcholine receptor modulators}}
{{Serotonin receptor modulators}}
}}
{{Tetracyclics}}


]
] ]
]

Latest revision as of 00:35, 21 March 2024

Class of pharmaceutical drugs Not to be confused with Tetracycline or Tricyclic antidepressant.
Chemical structure of the TeCA mirtazapine. Notice its four rings fused together.

Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their tetracyclic chemical structure, containing four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.

List of TeCAs

Marketed

Drugs that contain four rings not all fused together but are sometimes still classified as TeCAs include:

Miscellaneous

  • Benzoctamine (Tacitin) – a tetracyclic compound and is closely related to maprotiline, with the two compounds differing only in the length of their side chain, but benzoctamine is not used as an antidepressant and is instead used as an anxiolytic
  • Loxapine (Adasuve, Loxitane) – a typical antipsychotic that produces amoxapine as a major metabolite and is said to have antidepressant effects, but it is not usually regarded as a TeCA

Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:

Never marketed

Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:

  • Ciclazindol (WY-23,409) – a close analogue of mazindol

Pharmacology

See also: Pharmacology of antidepressants

TeCAs have diverse pharmacology and differ from TCAs in a number of ways. With the exception of amoxapine, TeCAs do not inhibit the reuptake of serotonin. However, aside from mirtazapine, they do inhibit the reuptake of norepinephrine. TeCAs block the serotonin 5-HT2 receptors similarly to TCAs. Besides mirtazapine, they also block the α1-adrenergic receptor. Conversely, whereas TCAs have relatively low affinity for the α2-adrenergic receptor, mianserin and mirtazapine potently antagonize this receptor, and this action is thought to be involved in their antidepressant effects. TeCAs block the histamine H1 receptor similarly to the TCAs, but tend to be even stronger antihistamines than TCAs. On the other hand, in contrast to almost all TCAs, TeCAs have only low affinity for the muscarinic acetylcholine receptors, and for this reason, are associated with few or no anticholinergic side effects. Mianserin and mirtazapine are far less toxic than TCAs in overdose.

Binding profiles

See also: Tricyclic antidepressant § Binding profiles

The binding profiles of various TeCAs in terms of their affinities (Ki, nM) for various receptors and transporters are as follows:

Compound SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter 5-HT1A 5-HT2A 5-HT2B 5-HT2C 5-HT3 5-HT6 5-HT7 α1 α2 D2 H1 H2 mAChTooltip Muscarinic acetylcholine receptor
Amoxapine 58 16 4,310 ND 0.5 ND 2.0 ND 6.0–50 41 50 2,600 3.6–160 7.9–25 ND 1,000
Maprotiline 5,800 11–12 1,000 ND 51 ND 122 ND ND 50 90 9,400 350–665 0.79–2.0 776 570
Mianserin 4,000 71 9,400 400–2,600 1.6–20 1.6–55 0.63–6.5 5.8–300 55–81 48–56 34 3.8–73 ≥2,100 0.30–1.7 437 820
Mirtazapine >10,000 ≥4,600 >10,000 ≥3,330 6.3–69 200 8.9–39 7.9 ND 265 316–1,815 18–88 >5,454 0.14–1.6 >10,000 670
Setiptiline >10,000 220 >10,000 ND ND ND ND ND ND ND ND 24 ND ND ND ND
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.

The TeCAs act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters.

See also

References

  1. Shaw, W. L. (1980-01-01). "The comparative safety of mianserin in overdose". Current Medical Research and Opinion. 6 (sup7): 44–51. doi:10.1185/03007998009114803. ISSN 0300-7995.
  2. Waring, W. Stephen; Good, Alison M.; Bateman, D. Nicholas (2007-01-01). "Lack of significant toxicity after mirtazapine overdose: A five-year review of cases admitted to a regional toxicology unit". Clinical Toxicology. 45 (1): 45–50. doi:10.1080/15563650601005837. ISSN 1556-3650. PMID 17357381. S2CID 28546654.
  3. Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
Antidepressants (N06A)
Specific reuptake inhibitors and/or receptor modulators
SSRIsTooltip Selective serotonin reuptake inhibitors
SNRIsTooltip Serotonin–norepinephrine reuptake inhibitors
NRIsTooltip Norepinephrine reuptake inhibitors
NDRIsTooltip Norepinephrine–dopamine reuptake inhibitors
NaSSAsTooltip Noradrenergic and specific serotonergic antidepressants
SARIsTooltip Serotonin antagonist and reuptake inhibitors
SMSTooltip Serotonin modulator and stimulators
Others
Tricyclic and tetracyclic antidepressants
TCAsTooltip Tricyclic antidepressants
TeCAsTooltip Tetracyclic antidepressants
Others
Monoamine oxidase inhibitors
Non-selective
MAOATooltip Monoamine oxidase A-selective
MAOBTooltip Monoamine oxidase B-selective
Adjunctive therapies
Miscellaneous
Pharmacodynamics
Adrenergic receptor modulators
α1
Agonists
Antagonists
α2
Agonists
Antagonists
β
Agonists
Antagonists
Dopamine receptor modulators
D1-like
Agonists
PAMs
Antagonists
D2-like
Agonists
Antagonists
Histamine receptor modulators
H1
Agonists
Antagonists
H2
Agonists
Antagonists
H3
Agonists
Antagonists
H4
Agonists
Antagonists
See also
Receptor/signaling modulators
Monoamine metabolism modulators
Monoamine reuptake inhibitors
Monoamine reuptake inhibitors
DATTooltip Dopamine transporter
(DRIsTooltip Dopamine reuptake inhibitors)
NETTooltip Norepinephrine transporter
(NRIsTooltip Norepinephrine reuptake inhibitors)
SERTTooltip Serotonin transporter
(SRIsTooltip Serotonin reuptake inhibitors)
VMATsTooltip Vesicular monoamine transporters
Others
See also: Receptor/signaling modulators • Monoamine releasing agents • Adrenergics • Dopaminergics • Serotonergics • Monoamine metabolism modulators • Monoamine neurotoxins
Muscarinic acetylcholine receptor modulators
mAChRsTooltip Muscarinic acetylcholine receptors
Agonists
Antagonists
Precursors
(and prodrugs)
See also
Receptor/signaling modulators
Nicotinic acetylcholine receptor modulators
Acetylcholine metabolism/transport modulators
Serotonin receptor modulators
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT3–7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
Tetracyclics
Classes

Steroids

Antibiotics
Antidepressants
(TeCAs)
Steroids
Categories: