Tandospirone

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. although at higher doses more rapid anxiolytic responses have been seen. It has also been used successfully as a treatment for bruxism.

Augmentation for depression

Tandospirone can be used as an effective augmentation, especially when coupled with fluoxetine or clomipramine.

Other uses

Tandospirone might been tried successfully as an adjunctive treatment for cognitive symptoms in schizophrenic individuals.

Side effects

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.

Pharmacology

Pharmacodynamics

Tandospirone acts as a potent and selective 5-HT1A receptor partial agonist, with a Ki affinity value of 27 ± 5 nM and approximately 55 to 85% intrinsic activity. 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). 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). Tandospirone has been found to produce antiaggressive effects in rodents.

Chemistry

Synthesis

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

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. It was subsequently also introduced in China in 2004.

Society and culture

Name

Tandospirone is also known as metanopirone and by the developmental code name SM-3997. It is marketed in Japan under the brand name Sediel.

References

References

1. (February 1996). "Tandospirone". CNS Drugs.
2. (2004). "Tandospirone in the treatment of generalised anxiety disorder and mixed anxiety-depression : results of a comparatively high dosage trial". Clinical Drug Investigation.
3. (23 September 2011). "Martindale: The Complete Drug Reference". The Royal Pharmaceutical Society of Great Britain.
4. (November 2017). "Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms". Impact Journals, LLC.
5. (October 2001). "Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment". The American Journal of Psychiatry.
6. (July 1990). "Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites". Biological Psychiatry.
7. (December 1995). "Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain". General Pharmacology.
8. (2004). "Effects of tandospirone, a novel anxiolytic agent, on human 5-HT_1A receptors expressed in Chinese hamster ovary cells (CHO cells)". Biogenic Amines.
9. (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.
10. (October 1992). "Kinetics, brain uptake, and receptor binding of tandospirone and its metabolite 1-(2-pyrimidinyl)-piperazine". Journal of Clinical Psychopharmacology.
11. (July 1991). "Effects of serotonergic agents on isolation-induced aggression". Pharmacol Biochem Behav.
12. (July 1991). "Ethopharmacology of maternal aggression in mice: effects of diazepam and SM-3997". Eur J Pharmacol.
13. (April 1997). "[A new approach to innovating selective anxiolytics: pharmacological profile of a novel 5-HT1A agonist (tandospirone)]". Nihon Shinkei Seishin Yakurigaku Zasshi.
14. (March 1998). "Effect of 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a novel 5-HT1A-receptor agonist, on aggressive behavior and marble burying behavior in mice". Jpn J Pharmacol.
15. (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.
16. (1992). "An Efficient Synthesis of Buspirone and its Analogues.". Archiv der Pharmazie.
17. (1986). "SM-3997". Drugs of the Future.
18. {{cite patent
19. {{cite patent
20. (June 1992). "14C-labeling of a novel anxiolytic agent tandospirone". Journal of Labelled Compounds and Radiopharmaceuticals.
21. {{cite patent
22. (2012). "Anxiolytics". Birkhäuser Basel.
23. (2022). "NeuroPsychopharmacotherapy". Springer International Publishing.
24. (2014). "The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies". Springer US.
25. Schweizerischer Apotheker-Verein. (2004). "Index Nominum: International Drug Directory". Medpharm Scientific Publishers.
26. (2012). "Concise Dictionary of Pharmacological Agents: Properties and Synonyms". Springer Netherlands.