CT-005404
Chemical compound
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CT-005404, or CT-5404, is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil.[1][2][3] It shows pro-motivational effects in animals and reverses motivational deficits induced by tetrabenazine and interleukin-1β.[2][4][3] CT-005404 is described as being orally active in animals and having a long duration of action.[5][4][3] It is under development by Chronos Therapeutics for treatment of motivational disorders.[6][3] The drug was first described by 2018.[5][1][6][3]
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Moscoso M, Sanchez S (2019). "Society for Neuroscience – 48th Annual Meeting. San Diego, California, USA – November 3–7, 2018". Drugs of the Future. 44 (1): 93. doi:10.1358/dof.2019.44.1.2954217. The assessment of two other modafinil-based atypical DAT inhibitors, CT-005404 and CT-0050904, in the reversal of the [...]
Rotolo RA, Presby RE, Tracy O, Asar S, Yang JH, Correa M, et al. (February 2021). "The novel atypical dopamine transport inhibitor CT-005404 has pro-motivational effects in neurochemical and inflammatory models of effort-based dysfunctions related to psychopathology". Neuropharmacology. 183 108325. doi:10.1016/j.neuropharm.2020.108325. PMID 32956676. Treadway MT, Salamone JD (2022). Vigor, Effort-Related Aspects of Motivation and Anhedonia. Current Topics in Behavioral Neurosciences. Vol. 58. pp. 325–353. doi:10.1007/7854_2022_355. ISBN 978-3-031-09682-2. PMID 35505057. . Recent papers have assessed the effort-related effects of the novel atypical DAT inhibitors (S)-CE-123, (S,S)-CE158, and CT-005404. All three compounds reversed the low-effort bias induced by TBZ, and also increased selection of high-effort PROG lever pressing while decreasing chow intake (Rotolo et al. 2019, 2020, 2021). These compounds also produced modest but significant increases in extracellular DA in nucleus accumbens core, with CT-005404 having a particularly long-lasting effect. Moreover, CT-005404 also reversed the suppression of lever pressing induced by the pro-inflammatory cytokine IL-1β (Rotolo et al. 2021). Along with adenosine A2A antagonists such as istradefylline and preladenant (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018), and D1 agonists (Yohn et al. 2015b), atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms.
Salamone JD, Rotolo RA, Murray F, McNamara B, Presby RE, Yang JH, et al. (5 November 2018). 323.04 / AAA17 - The novel atypical dopamine transport inhibitors CT-005094 and CT-005404 reverse the effort-related motivational effects of the dopamine depleting agent tetrabenazine. Neuroscience 2018. Society for Neuroscience. The present studies focused on recently synthesized atypical DAT inhibitors, CT-005094 and CT-005404. These compounds bind to DAT with high selectivity relative to the serotonin and norepinephrine transporters, and can elevate extracellular levels of DA as measured by microdialysis without stimulating DA release. In the present studies, CT-005094 and CT-005404 were assessed for their ability to reverse the effort-related motivational effects of tetrabenazine. Rats were tested using the fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. CT-005094 was co-administered at doses ranging from 2.0-16.0 mg/kg IP, and the 8.0 mg/kg dose partially but significantly reversed the effects of tetrabenazine. CT-005404 was orally active, and reversed the effects of tetrabenazine in the dose range of 15.0-30.0 mg/kg PO. Atypical DAT inhibitors such as CT-005094 and CT-005404 offer potential as a new avenue for drug treatment of motivational dysfunctions in humans.