Tandospirone

Last updated
Tandospirone
Tandospirone.svg
Clinical data
Trade names Sediel
Other namesMetanopirone
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolites 1-PP Tooltip 1-(2-Pyrimidinyl)piperazine
Elimination half-life Tandospirone: 2–3 hours
1-PP Tooltip 1-(2-Pyrimidinyl)piperazine: 3–5 hours
Excretion Urine (70%; 0.1% as unchanged drug)
Identifiers
  • (1R,2R,6S,7S)-4-{4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl}-4-azatricyclo[5.2.1.02,6]decane-3,5-dione
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.210.461 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H29N5O2
Molar mass 383.496 g·mol−1
3D model (JSmol)
  • O=C1N(C(=O)[C@H]3[C@@H]1[C@@H]2CC[C@H]3C2)CCCCN5CCN(c4ncccn4)CC5
  • InChI=1S/C21H29N5O2/c27-19-17-15-4-5-16(14-15)18(17)20(28)26(19)9-2-1-8-24-10-12-25(13-11-24)21-22-6-3-7-23-21/h3,6-7,15-18H,1-2,4-5,8-14H2/t15-,16+,17+,18- Yes check.svgY
  • Key:CEIJFEGBUDEYSX-FZDBZEDMSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tandospirone, sold under the brand name Sediel, is an anxiolytic and antidepressant medication used in Japan and China, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone class of drugs and is closely related to other azapirones like buspirone and gepirone.

Contents

Tandospirone was introduced for medical use in Japan in 1996 [1] and in China in 2004. [2]

Medical uses

Anxiety and depression

Tandospirone is most commonly used as a treatment for anxiety and depressive disorders, such as generalised anxiety disorder and dysthymia respectively. [3] For both indications it usually takes a couple of weeks for therapeutic effects to begin to be seen, [3] although at higher doses more rapid anxiolytic responses have been seen. [4] It has also been used successfully as a treatment for bruxism. [5]

Augmentation for depression

Tandospirone can be used as an effective augmentation,[ clarification needed ] especially when coupled with fluoxetine or clomipramine. [6]

Other uses

Tandospirone has been tried successfully as an adjunctive treatment for cognitive symptoms[ clarification needed ] in schizophrenic individuals. [7]

Side effects

Common adverse effects include: [3] [1]

Adverse effects with unknown frequency include: [3]

It is not believed to be addictive but is known to produce mild withdrawal effects (e.g., anorexia) after abrupt discontinuation. [3]

Pharmacology

Pharmacodynamics

Tandospirone acts as a potent and selective 5-HT1A receptor partial agonist, with a Ki affinity value of 27 ± 5 nM [8] and approximately 55 to 85% intrinsic activity. [9] [10] It has relatively weak affinity for the 5-HT2A (1,300 ± 200), 5-HT2C (2,600 ± 60), α1-adrenergic (1,600 ± 80), α2-adrenergic (1,900 ± 400), D1 (41,000 ± 10,000), and D2 (1,700 ± 300) receptors, and is essentially inactive at the 5-HT1B, 5-HT1D, β-adrenergic, and muscarinic acetylcholine receptors, serotonin transporter, and benzodiazepine allosteric site of the GABAA receptor (all of which are > 100,000). [8] There is evidence of tandospirone having low but significant antagonistic activity at the α2-adrenergic receptor through its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP). [11] [12]

Chemistry

Synthesis

Thieme Synthesis: .mw-parser-output .citation{word-wrap:break-word}.mw-parser-output .citation:target{background-color:rgba(0,127,255,0.133)} EP 0082402, Ishizumi K, Antoku F, Asami Y, published 1986, assigned to Sumitomo Chemical Company, Limited) </ref> pubdate = 2010 CN 101880274A pubdate = 2010, Zhang J, Li L, assigned to \PKUCare Southwest Synthetic Pharmaceutical Corp., Ltd. </ref> Radiolabelled: Mannich reaction method: Tandospirone synthesis.svg
Thieme Synthesis: EP 0082402,Ishizumi K, Antoku F, Asami Y,published 1986, assigned to Sumitomo Chemical Company, Limited) </ref> pubdate = 2010 CN 101880274A pubdate = 2010,Zhang J, Li L, assigned to \PKUCare Southwest Synthetic Pharmaceutical Corp., Ltd. </ref> Radiolabelled: Mannich reaction method:

The catalytic hydrogenation of cis-5-Norbornene-exo-2,3-dicarboxylic anhydride [129-64-6] (1) gives Norbornane-2exo,3exo-dicarboxylic Acid-anhydride [14166-28-0] (2). Reaction with aqueous ammonia leads to Exo-2,3-norbornanedicarboximide [14805-29-9] (3). Alkylation with 1,4-dibromobutane [110-52-1] (4) gives CID:10661911 (5). Alkylation of the remaining halogen with 2-(1-Piperazinyl)Pyrimidine [20980-22-7] (6) completed the synthesis of Tandospirone (7).

History

Tandospirone was introduced in Japan for the treatment of anxiety disorders in 1996. [1] It was subsequently also introduced in China in 2004. [2]

Society and culture

Name

Tandospirone is also known as metanopirone and by the developmental code name SM-3997. [18] [19] [20] [5] It is marketed in Japan under the brand name Sediel. [18] [19] [20] [5]

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Azapirone</span> Drug class of psycotropic drugs

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

<span class="mw-page-title-main">Buspirone</span> Medication used to treat anxiety disorders

Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. Benefits support its short-term use. It is taken orally, and takes two to six weeks to be fully effective.

<span class="mw-page-title-main">Trazodone</span> Chemical compound, antidepressant medication

Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and difficulties with sleep. The medication is taken orally.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

<span class="mw-page-title-main">Ipsapirone</span> Chemical compound

Ipsapirone is a selective 5-HT1A receptor partial agonist of the piperazine and azapirone chemical classes. It has antidepressant and anxiolytic effects. Ipsapirone was studied in several placebo-controlled trials for depression and continues to be used in research.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<i>meta</i>-Chlorophenylpiperazine Stimulant

meta-Chlorophenylpiperazine (mCPP) is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a designer drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as "ecstasy" in Europe and the United States.

<span class="mw-page-title-main">Gepirone</span> Medication

Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarisation and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

<span class="mw-page-title-main">Deramciclane</span> Chemical compound

Deramciclane (EGIS-3886) is a non-benzodiazepine-type anxiolytic drug to treat various types of anxiety disorders. Deramciclane is a unique alternative to current anxiolytics on the market because it has a novel chemical structure and target. It acts as an antagonist at the 5-HT2A receptor, as an inverse agonist at the 5-HT2C receptor, and as a GABA reuptake inhibitor. The two serotonin receptors are G protein-coupled receptors and are two of the main excitatory serotonin receptor types. Their excitation has been implicated in anxiety and mood. Deramciclane does not affect CYP3A4 activity in metabolizing other drugs, but it is a weak inhibitor of CYP2D6. Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to dopamine receptor D1. Researchers are looking for alternatives to benzodiazepines for anxiolytic use because benzodiazepine drugs have sedative and muscle relaxant side effects.

<span class="mw-page-title-main">Alnespirone</span> Chemical compound

Alnespirone (S-20,499) is a selective 5-HT1A receptor full agonist of the azapirone chemical class. It has antidepressant and anxiolytic effects.

<span class="mw-page-title-main">Pyrimidinylpiperazine</span> Chemical compound

1-(2-Pyrimidinyl)piperazine (1-PP, 1-PmP) is a chemical compound and piperazine derivative. It is known to act as an antagonist of the α2-adrenergic receptor (Ki = 7.3–40 nM) and, to a much lesser extent, as a partial agonist of the 5-HT1A receptor (Ki = 414 nM; Emax = 54%). It has negligible affinity for the dopamine D2, D3, and D4 receptors (Ki > 10,000 nM) and does not appear to have significant affinity for the α1-adrenergic receptors. Its crystal structure has been determined.

<span class="mw-page-title-main">Eptapirone</span> Chemical compound

Eptapirone (F-11,440) is a very potent and highly selective 5-HT1A receptor full agonist of the azapirone family. Its affinity for the 5-HT1A receptor was reported to be 4.8 nM (Ki), and its intrinsic activity approximately equal to that of serotonin.

<span class="mw-page-title-main">Tiospirone</span> Pharmaceutical drug

Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class. It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent to those of typical antipsychotics in clinical trials but without causing extrapyramidal side effects. However, development was halted and it was not marketed. Perospirone, another azapirone derivative with antipsychotic properties, was synthesized and assayed several years after tiospirone. It was found to be both more potent and more selective in comparison and was commercialized instead.

<span class="mw-page-title-main">Revospirone</span> Chemical compound

Revospirone is an azapirone drug which was patented as a veterinary tranquilizer but was never marketed. It acts as a selective 5-HT1A receptor partial agonist. Similarly to other azapirones such as buspirone, revospirone produces 1-(2-pyrimidinyl)piperazine (1-PP) as an active metabolite. As a result, it also acts as an α2-adrenergic receptor antagonist to an extent.

<span class="mw-page-title-main">Umespirone</span> Chemical compound

Umespirone (KC-9172) is a drug of the azapirone class which possesses anxiolytic and antipsychotic properties. It behaves as a 5-HT1A receptor partial agonist (Ki = 15 nM), D2 receptor partial agonist (Ki = 23 nM), and α1-adrenoceptor receptor antagonist (Ki = 14 nM), and also has weak affinity for the sigma receptor (Ki = 558 nM). Unlike many other anxiolytics and antipsychotics, umespirone produces minimal sedation, cognitive/memory impairment, catalepsy, and extrapyramidal symptoms.

<span class="mw-page-title-main">Pardoprunox</span> Antiparkinsonian compound researched for the treatment of depression and anxiety disorders

Pardoprunox (INN) is an antiparkinsonian drug developed by Solvay for the treatment of Parkinson's disease that reached phase III clinical trials before being discontinued. It was also being investigated for the treatment of depression and anxiety but these indications appear to have been abandoned as well.

<span class="mw-page-title-main">Lesopitron</span> Chemical compound

Lesopitron (E-4424) is a selective full agonist of the 5-HT1A receptor which is structurally related to the azapirones. In 2001 it was under development by Esteve as an anxiolytic for the treatment of generalized anxiety disorder (GAD). It made it to phase II clinical trials but was apparently discontinued as no new information on lesopitron has surfaced since.

<span class="mw-page-title-main">Osemozotan</span> Pharmaceutical drug

Osemozotan (MKC-242) is a selective 5-HT1A receptor agonist with some functional selectivity, acting as a full agonist at presynaptic and a partial agonist at postsynaptic 5-HT1A receptors. 5-HT1A receptor stimulation influences the release of various neurotransmitters including serotonin, dopamine, norepinephrine, and acetylcholine. 5-HT1A receptors are inhibitory G protein-coupled receptor. Osemozotan has antidepressant, anxiolytic, antiobsessional, serenic, and analgesic effects in animal studies, and is used to investigate the role of 5-HT1A receptors in modulating the release of dopamine and serotonin in the brain, and their involvement in addiction to abused stimulants such as cocaine and methamphetamine.

References

  1. 1 2 3 4 Levine LR, Potter WZ (2012). "The 5-HT1A receptor: an unkept promise". In Briley M, Nutt D (eds.). Anxiolytics. Milestones in Drug Therapy. Birkhäuser Basel. p. 99. ISBN   978-3-0348-8470-9 . Retrieved 2023-10-07.
  2. 1 2 Riederer P, Laux G, Nagatsu T, Le W, Riederer C (2022). NeuroPsychopharmacotherapy. Springer International Publishing. p. 2131. ISBN   978-3-030-62059-2 . Retrieved 2023-10-07.
  3. 1 2 3 4 5 6 Barradell LB, Fitton A (February 1996). "Tandospirone". CNS Drugs. 5 (2): 147–153. doi:10.2165/00023210-199605020-00006.
  4. ↑ Nishitsuji K, To H, Murakami Y, Kodama K, Kobayashi D, Yamada T, et al. (2004). "Tandospirone in the treatment of generalised anxiety disorder and mixed anxiety-depression : results of a comparatively high dosage trial". Clinical Drug Investigation. 24 (2): 121–126. doi:10.2165/00044011-200424020-00007. PMID   17516698. S2CID   38339009.
  5. 1 2 3 "Tandospirone". Martindale: The Complete Drug Reference. The Royal Pharmaceutical Society of Great Britain. 23 September 2011. Retrieved 14 November 2013.
  6. ↑ Huang X, Yang J, Yang S, Cao S, Qin D, Zhou Y, et al. (November 2017). "Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms". Oncotarget. Impact Journals, LLC. 8 (60): 102705–102720. doi:10.18632/oncotarget.22170. PMC   5731992 . PMID   29254282.
  7. ↑ Sumiyoshi T, Matsui M, Nohara S, Yamashita I, Kurachi M, Sumiyoshi C, et al. (October 2001). "Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment". The American Journal of Psychiatry. 158 (10): 1722–1725. doi:10.1176/appi.ajp.158.10.1722. PMID   11579010.
  8. 1 2 Hamik A, Oksenberg D, Fischette C, Peroutka SJ (July 1990). "Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites". Biological Psychiatry. 28 (2): 99–109. doi:10.1016/0006-3223(90)90627-E. PMID   1974152. S2CID   25608914.
  9. ↑ Tanaka H, Tatsuno T, Shimizu H, Hirose A, Kumasaka Y, Nakamura M (December 1995). "Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain". General Pharmacology. 26 (8): 1765–1772. doi:10.1016/0306-3623(95)00077-1. PMID   8745167.
  10. ↑ Yabuuchi K, Tagashira R, Ohno Y (2004). "Effects of tandospirone, a novel anxiolytic agent, on human 5-HT1A receptors expressed in Chinese hamster ovary cells (CHO cells)". Biogenic Amines. 18 (3): 319–328. doi:10.1163/1569391041501933.
  11. ↑ Blier P, Curet O, Chaput Y, de Montigny C (July 1991). "Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission". Neuropharmacology. 30 (7): 691–701. doi:10.1016/0028-3908(91)90176-C. PMID   1681447. S2CID   44297577.
  12. ↑ Miller LG, Thompson ML, Byrnes JJ, Greenblatt DJ, Shemer A (October 1992). "Kinetics, brain uptake, and receptor binding of tandospirone and its metabolite 1-(2-pyrimidinyl)-piperazine". Journal of Clinical Psychopharmacology. 12 (5): 341–345. doi:10.1097/00004714-199210000-00009. PMID   1362206. S2CID   22449352.
  13. ↑ Ishizumi K, Kojima A, Antoku F (September 1991). "Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (tandospirone) and related compounds". Chemical & Pharmaceutical Bulletin. 39 (9): 2288–2300. doi: 10.1248/cpb.39.2288 . eISSN   1347-5223. PMID   1687114.
  14. ↑ Cybulski J, Chilmonczyk Z, Szelejewski W, Wojtasiewicz K, Wróbel JT (1992). "An Efficient Synthesis of Buspirone and its Analogues". Archiv der Pharmazie. 325 (5): 313–315. doi:10.1002/ardp.19923250513. eISSN   1521-4184. ISSN   0365-6233. S2CID   83676454.
  15. ↑ Prous J, Castaner J (1986). "SM-3997". Drugs of the Future. 11 (11): 949. doi:10.1358/dof.1986.011.11.53048.
  16. ↑ Nishioka K, Kanamaru H (June 1992). "14C-labeling of a novel anxiolytic agent tandospirone". Journal of Labelled Compounds and Radiopharmaceuticals. 31 (6): 427–436. doi:10.1002/jlcr.2580310602. ISSN   0362-4803.
  17. ↑ WO 2012016569,Hansen JB, Thomsen MS, assigned to Conrig Pharma ApS
  18. 1 2 Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 1149. ISBN   978-1-4757-2085-3 . Retrieved 2023-10-07.
  19. 1 2 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 1146. ISBN   978-3-88763-101-7 . Retrieved 2023-10-07.
  20. 1 2 Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 257. ISBN   978-94-011-4439-1 . Retrieved 2023-10-07.
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