Tipepidine

• CAT Number: I037325
• CAS Number: 5169-78-8
• Molecular Formula: C15H17NS2
• Molecular Weight: 275.43
• Purity: 98%
• Synonyms: Tipepidine; AT 327; AT-327; AT327; brand names Asverin, Antupex, Asvelik, Asvex, Bitiodin, Cofdenin A, Hustel, Nodal, Sotal.
• Target: Potassium Channel
• Solubility: Soluble in DMSO
• Appearance: Solid powder
• Storage: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
• IUPAC Name: 3-(Di-2-thienylmethylene)-1-methylpiperidine
• 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
• InChIKey: JWIXXNLOKOAAQT-UHFFFAOYSA-N
• SMILES: CN1C/C(CCC1)=C(C2=CC=CS2)C3=CC=CS3

Tipepidine (Cat.No:I037325), also known as tipepidine hibenzate, is a synthetic, non-opioid antitussive and expectorant of the thiambutene class. It acts as an inhibitor of G protein-coupled inwardly-rectifying potassium channels (GIRKs). Tipepidine has recently garnered interest as a potential psychiatric drug. It is being investigated in depression, obsessive-compulsive disorder, and attention-deficit hyperactivity disorder (ADHD). 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.

Reference

1: Dehbozorghi S, Bagheri S, Moradi K, Shokraee K, Mohammadi MR, Akhondzadeh S. Efficacy and safety of tipepidine as adjunctive therapy in children with attention-deficit/hyperactivity disorder: Randomized, double-blind, placebo- controlled clinical trial. Psychiatry Clin Neurosci. 2019 Nov;73(11):690-696. doi: 10.1111/pcn.12913. Epub 2019 Aug 3. PMID: 31294924.
2: Nageye F, Cortese S. Beyond stimulants: a systematic review of randomised controlled trials assessing novel compounds for ADHD. Expert Rev Neurother. 2019 Jul;19(7):707-717. doi: 10.1080/14737175.2019.1628640. Epub 2019 Jun 26. PMID: 31167583.
3: Fukuda H, Suzuki T, Hashizaki K, Yoshimura S, Kobayashi C, Omotani Y, Suzuki N, Kanazawa T, Fukami T, Yamamoto Y. [Optimum Volume of Water Needed for the Paste State of Pediatric Powders: Considerations Based on Yield Values and Applications to Generic Medicine]. Yakugaku Zasshi. 2019;139(2):299-308. Japanese. doi: 10.1248/yakushi.18-00182. PMID: 30713242.
4: Miki R, Honda I, Hamasaki R, Kawahara R, Soeda F, Shirasaki T, Misumi S, Takahama K. Effects of tipepidine on MK-801-induced cognitive impairment in mice. Brain Res. 2019 May 1;1710:230-236. doi: 10.1016/j.brainres.2018.12.032. Epub 2018 Dec 22. PMID: 30584927.
5: Shah R, Verma PK. Therapeutic importance of synthetic thiophene. Chem Cent J. 2018 Dec 19;12(1):137. doi: 10.1186/s13065-018-0511-5. PMID: 30564984; PMCID: PMC6768136.
6: Takai H, Kato I, Mitsunaga K, Hara M, Kodama T, Kanazawa M, Terai M. A pediatric case of anaphylactic shock induced by tipepidine hibenzate (Asverin). Asia Pac Allergy. 2018 Oct 18;8(4):e37. doi: 10.5415/apallergy.2018.8.e37. PMID: 30402404; PMCID: PMC6209596.
7: Honda I, Araki K, Honda S, Soeda F, Shin MC, Misumi S, Yamamura KI, Takahama K. Deletion of GIRK2 subunit containing GIRK channels of neurons expressing dopamine transporter decrease immobility time on forced swimming in mice. Neurosci Lett. 2018 Feb 5;665:140-146. doi: 10.1016/j.neulet.2017.11.028. Epub 2017 Nov 24. PMID: 29180115.
8: Soeda F, Fujieda Y, Kinoshita M, Shirasaki T, Takahama K. Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels. Pharmacol Biochem Behav. 2016 May;144:26-32. doi: 10.1016/j.pbb.2016.02.006. Epub 2016 Feb 16. PMID: 26892760.
9: Kawaura K, Ogata Y, Honda S, Soeda F, Shirasaki T, Takahama K. Tipepidine, a non-narcotic antitussive, exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone-treated rats. Behav Brain Res. 2016 Apr 1;302:269-78. doi: 10.1016/j.bbr.2015.12.008. Epub 2015 Dec 29. PMID: 26738969.
10: Tomoda A, Takiguchi S, Fujisawa TX, Yatsuga C, Kumazaki H, Fujioka T, Suzuki H, Matsuzaki H, Kosaka H, Tanaka S. Effectiveness of oral tipepidine administration for children with attention deficit/hyperactivity disorder: A 4-week, open-label clinical study. Psychiatry Clin Neurosci. 2015 Oct;69(10):658-9. doi: 10.1111/pcn.12336. Epub 2015 Sep 2. PMID: 26332734.
11: Shirayama Y, Suzuki M, Takahashi M, Sato K, Hashimoto K. Effects of add-on tipepidine on treatment-resistant depression: an open-label pilot trial. Acta Neuropsychiatr. 2016 Feb;28(1):51-4. doi: 10.1017/neu.2015.43. Epub 2015 Jul 20. PMID: 26189506.
12: Nakai N, Sugiura K, Akiyama M, Katoh N. Acute generalized exanthematous pustulosis caused by dihydrocodeine phosphate in a patient with psoriasis vulgaris and a heterozygous IL36RN mutation. JAMA Dermatol. 2015 Mar;151(3):311-5. doi: 10.1001/jamadermatol.2014.3002. PMID: 25409173.
13: Hamao K, Kawaura K, Soeda F, Hamasaki R, Shirasaki T, Takahama K. Tipepidine increases dopamine level in the nucleus accumbens without methamphetamine-like behavioral sensitization. Behav Brain Res. 2015 May 1;284:118-24. doi: 10.1016/j.bbr.2015.02.012. Epub 2015 Feb 14. PMID: 25687844.
14: Mochizuki E, Shirai T, Noguchi R, Mitsui C, Taniguchi M, Suda T. Anaphylaxis caused by tipepidine hibenzate, a central antitussive drug. Respirol Case Rep. 2015 Mar;3(1):3-5. doi: 10.1002/rcr2.85. Epub 2014 Dec 2. PMID: 25802739; PMCID: PMC4364787.
15: Hashimoto K, Sasaki T. Old drug tipepidine as new hope for children with ADHD. Aust N Z J Psychiatry. 2015 Feb;49(2):181-2. doi: 10.1177/0004867414553952. Epub 2014 Oct 3. PMID: 25280911.
16: 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. Tipepidine in adolescent patients with depression: a 4 week, open-label, preliminary study. Neuropsychiatr Dis Treat. 2014 May 5;10:719-22. doi: 10.2147/NDT.S63075. PMID: 24833905; PMCID: PMC4015794.
17: 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. Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study. Neuropsychiatr Dis Treat. 2014 Jan 24;10:147-51. doi: 10.2147/NDT.S58480. PMID: 24493927; PMCID: PMC3908907.
18: Hamasaki R, Shirasaki T, Soeda F, Takahama K. Tipepidine activates VTA dopamine neuron via inhibiting dopamine D₂ receptor-mediated inward rectifying K⁺ current. Neuroscience. 2013 Nov 12;252:24-34. doi: 10.1016/j.neuroscience.2013.07.044. Epub 2013 Jul 26. PMID: 23896570.
19: Kawahara R, Soeda F, Kawaura K, Honda S, Miki R, Noguchi T, Shirasaki T, Takahama K. Effect of tipepidine with novel antidepressant-like action on c-fos- like protein expression in rat brain. Brain Res. 2013 Jun 4;1513:135-42. doi: 10.1016/j.brainres.2013.03.034. Epub 2013 Mar 30. PMID: 23548603.
20: Kawaura K, Miki R, Urashima Y, Kawahara R, Soeda F, Shirasaki T, Takahama K. Pharmacological mechanisms of antidepressant-like effect of tipepidine in the forced swimming test. Behav Brain Res. 2012 Jan 15;226(2):381-5. doi: 10.1016/j.bbr.2011.09.031. Epub 2011 Oct 5. PMID: 21995940.