Tipepidine

Tipepidine
Clinical data
AHFS/Drugs.com	International Drug Names
Routes of; administration	Oral
ATC code	R05DB24 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only) ;
Identifiers
	IUPAC name 3-(di-2-thienylmethylene)-1-methylpiperidine;
CAS Number	5169-78-8 ;
PubChem CID	5484;
ChemSpider	5284 ;
UNII	2260ZP67IT;
KEGG	D08604 ;
CompTox Dashboard (EPA)	DTXSID2022626 ;
Chemical and physical data
Formula	C15H17NS2
Molar mass	275.434 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES s1cccc1/C(c2sccc2)=C3\CCCN(C)C3;
	InChI InChI=1S/C15H17NS2/c1-16-8-2-5-12(11-16)15(13-6-3-9-17-13)14-7-4-10-18-14/h3-4,6-7,9-10H,2,5,8,11H2,1H3 ; Key:JWIXXNLOKOAAQT-UHFFFAOYSA-N ;
(verify)

Tipepidine (INN) (brand names Asverin, Antupex, Asvelik, Asvex, Bitiodin, Cofdenin A, Hustel, Nodal, Sotal), also known as tipepidine hibenzate (JAN), is a synthetic, non-opioid antitussive and expectorant of the thiambutene class.[1][2] It acts as an inhibitor of G protein-coupled inwardly-rectifying potassium channels (GIRKs).[3] The drug was discovered in the 1950s,[4] and was developed in Japan in 1959.[5] It is used as the hibenzate and citrate salts.[1][5]

The usual dose is 20 mg every 4–6 hours. Possible side effects of tipepidine, especially in overdose, may include drowsiness, vertigo, delirium, disorientation, loss of consciousness, and confusion.[5]

Tipepidine has recently garnered interest as a potential psychiatric drug. It is being investigated in depression,[3][6][7] obsessive-compulsive disorder,[8] and attention-deficit hyperactivity disorder (ADHD).[9][10][11] Through inhibition of GIRK channels, tipepidine increases dopamine levels in the nucleus accumbens, but without increasing locomotor activity or producing methamphetamine-like behavioral sensitization, and this action appears to be at least partly responsible for its antidepressant-like effects in rodents.[12][13]

References

C.R. Ganellin; David J. Triggle (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 1988–. ISBN 978-0-412-46630-4.
Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 1649–. ISBN 978-3-88763-075-1.
Kawaura, Kazuaki; Ogata, Yukino; Inoue, Masako; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo (2009). "The centrally acting non-narcotic antitussive tipepidine produces antidepressant-like effect in the forced swimming test in rats". Behavioural Brain Research. 205 (1): 315–318. doi:10.1016/j.bbr.2009.07.004. ISSN 0166-4328.
ES Patent 272195
Imai, Yuki; Ishii, Wakako; Endo, Ayumi; Arakawa, Chikako; Kohira, Ryutaro; Fujita, Yukihiko; Fuchigami, Tatsuo; Mugishima, Hideo (2011). "Tipepidine hibenzate intoxication". Pediatrics International. 53 (5): 779–781. doi:10.1111/j.1442-200X.2010.03297.x. ISSN 1328-8067.
KAWAURA, Kazuaki; HONDA, Sokichi; SOEDA, Fumio; SHIRASAKI, Tetsuya; TAKAHAMA, Kazuo (2010). "A Novel Antidepressant-like Action of Drugs Possessing GIRK Channel Blocking Action in Rats". Yakugaku Zasshi. 130 (5): 699–705. doi:10.1248/yakushi.130.699. ISSN 0031-6903.
Sasaki T, Hashimoto K, Tachibana M, Kurata T, Kimura H, Komatsu H, Ishikawa M, Hasegawa T, Shiina A, Hashimoto T, Kanahara N, Shiraishi T, Iyo M (2014). "Tipepidine in adolescent patients with depression: a 4 week, open-label, preliminary study". Neuropsychiatr Dis Treat. 10: 719–22. doi:10.2147/NDT.S63075. PMC 4015794. PMID 24833905.
Honda, Sokichi; Kawaura, Kazuaki; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo (2011). "The potent inhibitory effect of tipepidine on marble-burying behavior in mice". Behavioural Brain Research. 216 (1): 308–312. doi:10.1016/j.bbr.2010.08.010. ISSN 0166-4328. PMID 20713091.
Sasaki T, Hashimoto K, Tachibana M, Kurata T, Okawada K, Ishikawa M, Kimura H, Komatsu H, Ishikawa M, Hasegawa T, Shiina A, Hashimoto T, Kanahara N, Shiraishi T, Iyo M (2014). "Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study". Neuropsychiatr Dis Treat. 10: 147–51. doi:10.2147/NDT.S58480. PMC 3908907. PMID 24493927.
Hashimoto, K.; Sasaki, T. (2014). "Old drug tipepidine as new hope for children with ADHD". Australian & New Zealand Journal of Psychiatry. 49 (2): 181–182. doi:10.1177/0004867414553952. ISSN 0004-8674.
Dehbozorghi, S.; Bagheri, S.; Moradi, K.; Shokraee, K.; Mohammadi, M-R.; Akhondzadeh, S. (2019). "Efficacy and safety of tipepidine as adjunctive therapy in children with attention‐deficit/hyperactivity disorder: Randomized, double‐blind, placebo‐controlled clinical trial". Psychiatry and Clinical Neurosciences. 73 (11): 690–696. doi:10.1111/pcn.12913. ISSN 0912-2036.
Hamasaki R, Shirasaki T, Soeda F, Takahama K (2013). "Tipepidine activates VTA dopamine neuron via inhibiting dopamine D₂ receptor-mediated inward rectifying K⁺ current". Neuroscience. 252: 24–34. doi:10.1016/j.neuroscience.2013.07.044. PMID 23896570.
Hamao K, Kawaura K, Soeda F, Hamasaki R, Shirasaki T, Takahama K (2015). "Tipepidine increases dopamine level in the nucleus accumbens without methamphetamine-like behavioral sensitization". Behav. Brain Res. 284: 118–24. doi:10.1016/j.bbr.2015.02.012. PMID 25687844.

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[GanellinTriggle1996-1] C.R. Ganellin; David J. Triggle (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 1988–. ISBN 978-0-412-46630-4.

[2] Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 1649–. ISBN 978-3-88763-075-1.

[KawauraOgata2009-3] Kawaura, Kazuaki; Ogata, Yukino; Inoue, Masako; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo (2009). "The centrally acting non-narcotic antitussive tipepidine produces antidepressant-like effect in the forced swimming test in rats". Behavioural Brain Research. 205 (1): 315–318. doi:10.1016/j.bbr.2009.07.004. ISSN 0166-4328.

[4] ES Patent 272195

[ImaiIshii2011-5] Imai, Yuki; Ishii, Wakako; Endo, Ayumi; Arakawa, Chikako; Kohira, Ryutaro; Fujita, Yukihiko; Fuchigami, Tatsuo; Mugishima, Hideo (2011). "Tipepidine hibenzate intoxication". Pediatrics International. 53 (5): 779–781. doi:10.1111/j.1442-200X.2010.03297.x. ISSN 1328-8067.

[KAWAURAHONDA2010-6] KAWAURA, Kazuaki; HONDA, Sokichi; SOEDA, Fumio; SHIRASAKI, Tetsuya; TAKAHAMA, Kazuo (2010). "A Novel Antidepressant-like Action of Drugs Possessing GIRK Channel Blocking Action in Rats". Yakugaku Zasshi. 130 (5): 699–705. doi:10.1248/yakushi.130.699. ISSN 0031-6903.

[pmid24833905-7] Sasaki T, Hashimoto K, Tachibana M, Kurata T, Kimura H, Komatsu H, Ishikawa M, Hasegawa T, Shiina A, Hashimoto T, Kanahara N, Shiraishi T, Iyo M (2014). "Tipepidine in adolescent patients with depression: a 4 week, open-label, preliminary study". Neuropsychiatr Dis Treat. 10: 719–22. doi:10.2147/NDT.S63075. PMC 4015794. PMID 24833905.

[HondaKawaura2011-8] Honda, Sokichi; Kawaura, Kazuaki; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo (2011). "The potent inhibitory effect of tipepidine on marble-burying behavior in mice". Behavioural Brain Research. 216 (1): 308–312. doi:10.1016/j.bbr.2010.08.010. ISSN 0166-4328. PMID 20713091.

[pmid24493927-9] Sasaki T, Hashimoto K, Tachibana M, Kurata T, Okawada K, Ishikawa M, Kimura H, Komatsu H, Ishikawa M, Hasegawa T, Shiina A, Hashimoto T, Kanahara N, Shiraishi T, Iyo M (2014). "Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study". Neuropsychiatr Dis Treat. 10: 147–51. doi:10.2147/NDT.S58480. PMC 3908907. PMID 24493927.

[HashimotoSasaki2014-10] Hashimoto, K.; Sasaki, T. (2014). "Old drug tipepidine as new hope for children with ADHD". Australian & New Zealand Journal of Psychiatry. 49 (2): 181–182. doi:10.1177/0004867414553952. ISSN 0004-8674.

[pmid31294924-11] Dehbozorghi, S.; Bagheri, S.; Moradi, K.; Shokraee, K.; Mohammadi, M-R.; Akhondzadeh, S. (2019). "Efficacy and safety of tipepidine as adjunctive therapy in children with attention‐deficit/hyperactivity disorder: Randomized, double‐blind, placebo‐controlled clinical trial". Psychiatry and Clinical Neurosciences. 73 (11): 690–696. doi:10.1111/pcn.12913. ISSN 0912-2036.

[pmid23896570-12] Hamasaki R, Shirasaki T, Soeda F, Takahama K (2013). "Tipepidine activates VTA dopamine neuron via inhibiting dopamine D₂ receptor-mediated inward rectifying K⁺ current". Neuroscience. 252: 24–34. doi:10.1016/j.neuroscience.2013.07.044. PMID 23896570.

[pmid25687844-13] Hamao K, Kawaura K, Soeda F, Hamasaki R, Shirasaki T, Takahama K (2015). "Tipepidine increases dopamine level in the nucleus accumbens without methamphetamine-like behavioral sensitization". Behav. Brain Res. 284: 118–24. doi:10.1016/j.bbr.2015.02.012. PMID 25687844.

Tipepidine

See also

References