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Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced starting 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

• Maprotiline (Ludiomil) – can also be classified as a TCA and grouped with the secondary amines
• Mianserin (Tolvon)
• Mirtazapine (Remeron)
• Setiptiline (Tecipul)

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

• Amoxapine (Asendin) – often classified as a TCA and grouped with the secondary amines

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:

• Mazindol (Mazanor, Sanorex) – a monoamine reuptake inhibitor used as an appetite stimulant and with potential antidepressant effects, but not classified as a TeCA

Never marketed

• Aptazapine (CGS-7525A) – a close analogue of mirtazapine
• Esmirtazapine (ORG-50,081) – the (S)-(+) enantiomer of mirtazapine
• Oxaprotiline (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:

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

Pharmacology

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

The affinities (K_i (nM)) of a selection of TeCAs have been compared below at an assortment of binding sites:

The selected ligands act as antagonists (or inverse agonists depending on the site in question) at all receptors listed and as inhibitors of all transporters listed.

See also

• Noradrenergic and specific serotonergic antidepressant

References

1. Brunton, Laurence (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th Edition. China: McGraw-Hill. pp. 406–410. ISBN 978-0-07-162442-8.
2. Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2–3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
3. Wander TJ, Nelson A, Okazaki H, Richelson E (December 1986). "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro". European Journal of Pharmacology. 132 (2–3): 115–121. doi:10.1016/0014-2999(86)90596-0. PMID 3816971.
4. Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics. 230 (1): 94–102. PMID 6086881.
5. Tatsumi M, Jansen K, Blakely RD, Richelson E (March 1999). "Pharmacological profile of neuroleptics at human monoamine transporters". European Journal of Pharmacology. 368 (2–3): 277–283. doi:10.1016/S0014-2999(99)00005-9. PMID 10193665.
6. Wander TJ, Nelson A, Okazaki H, Richelson E (November 1987). "Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro". European Journal of Pharmacology. 143 (2): 279–282. doi:10.1016/0014-2999(87)90544-9. PMID 2891550.
7. Richelson E, Nelson A (August 1984). "Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro". European Journal of Pharmacology. 103 (3–4): 197–204. doi:10.1016/0014-2999(84)90478-3. PMID 6149136.
8. Fernández J, Alonso JM, Andrés JI, et al. (March 2005). "Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents". Journal of Medicinal Chemistry. 48 (6): 1709–12. doi:10.1021/jm049632c. PMID 15771415.
9. de Boer TH, Maura G, Raiteri M, de Vos CJ, Wieringa J, Pinder RM (April 1988). "Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers". Neuropharmacology. 27 (4): 399–408. doi:10.1016/0028-3908(88)90149-9. PMID 3419539.

• Chemical classes of psychoactive drugs
• Tetracyclic antidepressants