Tandospirone

Tandospirone is most commonly used as a treatment for anxiety and depressive disorders, such as generalised anxiety disorder and dysthymia respectively. For both indications it usually takes a couple of weeks for therapeutic effects to begin to be seen,{{cite journal | vauthors = Barradell LB, Fitton A |title=Tandospirone|journal=CNS Drugs|volume=5|issue=2|date=February 1996|pages=147–153|doi=10.2165/00023210-199605020-00006 }} although at higher doses more rapid anxiolytic responses have been seen.{{cite journal | vauthors = Nishitsuji K, To H, Murakami Y, Kodama K, Kobayashi D, Yamada T, Kubo C, Mine K | display-authors = 6 | title = Tandospirone in the treatment of generalised anxiety disorder and mixed anxiety-depression : results of a comparatively high dosage trial | journal = Clinical Drug Investigation | volume = 24 | issue = 2 | pages = 121–126 | year = 2004 | pmid = 17516698 | doi = 10.2165/00044011-200424020-00007 | s2cid = 38339009 }} It has also been used successfully as a treatment for bruxism.{{cite book| chapter = Tandospirone | title = Martindale: The Complete Drug Reference|publisher=The Royal Pharmaceutical Society of Great Britain|access-date=14 November 2013|date=23 September 2011| chapter-url=http://www.medicinescomplete.com/mc/martindale/current/10442-w.htm}}

Tandospirone can be used as an effective augmentation,{{clarify|date=July 2022}} especially when coupled with fluoxetine or clomipramine.{{cite journal | vauthors = Huang X, Yang J, Yang S, Cao S, Qin D, Zhou Y, Li X, Ye Y, Wu J | display-authors = 6 | title = Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms | journal = Oncotarget | volume = 8 | issue = 60 | pages = 102705–102720 | date = November 2017 | pmid = 29254282 | pmc = 5731992 | doi = 10.18632/oncotarget.22170 | publisher = Impact Journals, LLC }}

Tandospirone might been tried successfully as an adjunctive treatment for cognitive symptoms{{clarify|date=July 2022}} in schizophrenic individuals.{{cite journal | vauthors = Sumiyoshi T, Matsui M, Nohara S, Yamashita I, Kurachi M, Sumiyoshi C, Jayathilake K, Meltzer HY | display-authors = 6 | title = Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment | journal = The American Journal of Psychiatry | volume = 158 | issue = 10 | pages = 1722–1725 | date = October 2001 | pmid = 11579010 | doi = 10.1176/appi.ajp.158.10.1722 }}

Common adverse effects include:

• Dizziness
• Drowsiness
• Insomnia
• Headache
• Gastrointestinal disorders
• Dry mouth
• Negative influence on explicit memory function
• Nausea

Adverse effects with unknown frequency include:

• Hypotension (low blood pressure)
• Dysphoria
• Tachycardia
• Malaise
• Psychomotor impairment

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

Tandospirone acts as a potent and selective 5-HT_1A receptor partial agonist, with a K_i affinity value of 27 ± 5 nM{{cite journal | vauthors = Hamik A, Oksenberg D, Fischette C, Peroutka SJ | title = Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites | journal = Biological Psychiatry | volume = 28 | issue = 2 | pages = 99–109 | date = July 1990 | pmid = 1974152 | doi = 10.1016/0006-3223(90)90627-E | s2cid = 25608914 | doi-access = free }} and approximately 55 to 85% intrinsic activity.{{cite journal | vauthors = Tanaka H, Tatsuno T, Shimizu H, Hirose A, Kumasaka Y, Nakamura M | title = Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain | journal = General Pharmacology | volume = 26 | issue = 8 | pages = 1765–1772 | date = December 1995 | pmid = 8745167 | doi = 10.1016/0306-3623(95)00077-1 }}{{cite journal | vauthors = Yabuuchi K, Tagashira R, Ohno Y |title=Effects of tandospirone, a novel anxiolytic agent, on human 5-HT_1A receptors expressed in Chinese hamster ovary cells (CHO cells) |journal=Biogenic Amines |year=2004 |volume=18 |issue=3 |pages=319–328 |doi=10.1163/1569391041501933}} It has relatively weak affinity for the 5-HT_2A (1,300 ± 200), 5-HT_2C (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-HT_1B, 5-HT_1D, β-adrenergic, and muscarinic acetylcholine receptors, serotonin transporter, and benzodiazepine allosteric site of the GABA_A receptor (all of which are > 100,000). 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).{{cite journal | vauthors = Blier P, Curet O, Chaput Y, de Montigny C | title = 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 | journal = Neuropharmacology | volume = 30 | issue = 7 | pages = 691–701 | date = July 1991 | pmid = 1681447 | doi = 10.1016/0028-3908(91)90176-C | s2cid = 44297577 }}{{cite journal | vauthors = Miller LG, Thompson ML, Byrnes JJ, Greenblatt DJ, Shemer A | title = Kinetics, brain uptake, and receptor binding of tandospirone and its metabolite 1-(2-pyrimidinyl)-piperazine | journal = Journal of Clinical Psychopharmacology | volume = 12 | issue = 5 | pages = 341–345 | date = October 1992 | pmid = 1362206 | doi = 10.1097/00004714-199210000-00009 | s2cid = 22449352 }}

• The Noreximide [6319-06-8] precursor also has dual uses to make Taglutimide & Tripamide & Lurasidone.

File:Tandospirone synthesis.svg:{{cite journal | vauthors = Nishioka K, Kanamaru H | journal=Journal of Labelled Compounds and Radiopharmaceuticals | title=14C-labeling of a novel anxiolytic agent tandospirone | volume=31 | issue=6 | pages=427–436 | date= June 1992 | issn=0362-4803 | doi=10.1002/jlcr.2580310602}} Mannich reaction method:{{cite patent | inventor = Hansen JB, Thomsen MS | country = WO | number = 2012016569 | assign1 = Conrig Pharma ApS }}]]

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 [https://pubchem.ncbi.nlm.nih.gov/compound/10661911 CID:10661911] (5). Alkylation of the remaining halogen with 2-(1-Piperazinyl)Pyrimidine [20980-22-7] (6) completed the synthesis of Tandospirone (7).

Tandospirone was introduced in Japan for the treatment of anxiety disorders in 1996.{{cite book | vauthors = Levine LR, Potter WZ | chapter = The 5-HT1A receptor: an unkept promise | veditors = Briley M, Nutt D | title=Anxiolytics | publisher=Birkhäuser Basel | series=Milestones in Drug Therapy | year=2012 | isbn=978-3-0348-8470-9 | chapter-url = https://books.google.com/books?id=JZW-BwAAQBAJ&pg=PA99 | access-date=2023-10-07 | page=99}} It was subsequently also introduced in China in 2004.{{cite book | vauthors = Riederer P, Laux G, Nagatsu T, Le W, Riederer C | title=NeuroPsychopharmacotherapy | publisher=Springer International Publishing | year=2022 | isbn=978-3-030-62059-2 | url=https://books.google.com/books?id=G1qaEAAAQBAJ&pg=PA2131 | access-date=2023-10-07 | page=2131}}

Tandospirone is also known as metanopirone and by the developmental code name SM-3997.{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1149 | access-date=2023-10-07 | page=1149}}{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA1146 | access-date=2023-10-07 | page=1146}}{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA257 | access-date=2023-10-07 | page=257}} It is marketed in Japan under the brand name Sediel.

{{Reflist}}

{{Anxiolytics}}

{{Antidepressants}}

{{Adrenergic receptor modulators}}

{{Serotonin receptor modulators}}

Category:5-HT1A agonists

Category:Alpha-2 blockers

Category:Aminopyrimidines

Category:Antidepressants

Category:Anxiolytics

Category:Azapirones

Category:Cyclopentanes

Category:Imides

Category:1-(2-Pyrimidinyl)piperazines