CE-158 explained
| Class: | Atypical dopamine reuptake inhibitor |
| Pubchem: | 156150588 |
| Synonyms: | (S,S)-CE-158; S,S-CE-158 |
| Iupac Name: | 5-(3-bromophenyl)-phenylmethyl sulfinylmethyl-1,3-thiazole |
| C: | 17 |
| H: | 14 |
| Br: | 1 |
| N: | 1 |
| O: | 1 |
| S: | 2 |
| Smiles: | C1=CC=C(C=C1)C(C2=CC(=CC=C2)Br)S(=O)CC3=CN=CS3 |
| Stdinchi: | 1S/C17H14BrNOS2/c18-15-8-4-7-14(9-15)17(13-5-2-1-3-6-13)22(20)11-16-10-19-12-21-16/h1-10,12,17H,11H2 |
| Stdinchikey: | KWWHBBCVAQTAFQ-UHFFFAOYSA-N |
CE-158 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil.[1] [2] [3] [4] [5] It is often but not always referred to as the enantiopure enantiomer (S,S)-CE-158 instead.
CE-158 is a highly selective DRI with much greater potency than modafinil. As (S,S)-CE-158, its inhibitory potencies at the monoamine transporters are 227nM at the dopamine transporter (DAT), 11,970nM at the norepinephrine transporter (NET) (53-fold lower), and inactive at the serotonin transporter (SERT).
The drug shows pro-motivational effects in animals and reverses tetrabenazine-induced motivational deficits. It increases dopamine levels in the nucleus accumbens, blocks amphetamine-induced dopamine release in vitro, shows no effect on locomotor activity with acute or repeated administration except at a high dose, and enhances learning in animals.
CE-158 was first described by 2020. It is closely related to CE-123, an earlier modafinil analogue. CE-158 and related agents are of interest in the potential treatment of motivational disorders, psychostimulant use disorder (PSUD), and Alzheimer's disease.
See also
Notes and References
- Salamone JD, Correa M . The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine . Annu Rev Psychol . 75 . 1. 1–32 . January 2024 . 37788571 . 10.1146/annurev-psych-020223-012208 . Several atypical DAT inhibitors have been successful at reversing the effects of TBZ at doses that increase extracellular DA as measured by microdialysis, including CT-005404 (Rotolo et al. 2021), and the modafinil analogs CE-123 (Rotolo et al. 2019), CE-158 (Rotolo et al. 2020), and MK-26 (Kouhnavardi et al. 2022). [...] Furthermore, several drugs that inhibit DAT, when administered on their own, increase selection of high-effort PROG lever pressing in rats tested on the PROG/chow choice task, including bupropion (Randall et al. 2015); lisdexamfetamine (Yohn et al. 2016e); PRX-14040 (Yohn et al. 2016d); GBR 12909 (Yohn et al. 2016c); CE-123, CE-158, and CT-5404 (Rotolo et al. 2019, 2020, 2021); and MK-26 (Kouhnavardi et al. 2022).. 10234/207207 . free .
- Treadway MT, Salamone JD . Vigor, Effort-Related Aspects of Motivation and Anhedonia . Curr Top Behav Neurosci . Current Topics in Behavioral Neurosciences . 58 . 325–353 . 2022 . Cham . 35505057 . 10.1007/7854_2022_355 . 978-3-031-09682-2 . 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 [tetrabenazine (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, [...] atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms..
- Hersey M, Bartole MK, Jones CS, Newman AH, Tanda G . Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors . Molecules . 28 . 13 . July 2023 . 5270 . 37446929 . 10343811 . 10.3390/molecules28135270 . free . S,S-CE-158, a highly DAT-selective and atypical DAT inhibitor, demonstrated an ability to stabilize recognition memory during the information acquisition process in a dose-dependent manner in mice [193]. S,S-CE-158 induced a substantial and sustained increase in mice extracellular nucleus accumbens DA [193,194] but showed no significant effect on locomotor activity following acute or repeated exposure [194]. In addition, S,S-CE-158 attenuated the dopaminergic releasing effects of amphetamine in cells stably expressing hDAT and enhanced learning acquisition responses and neuronal activity in rats [194]. Furthermore, it was recently reported that only a high dose (20 mg/kg) of S,S-CE-158 increased locomotor activity in mice, and that a subthreshold dose (10 mg/kg) rescued motor learning deficits propagated by dopaminergic mGluR5 silencing, suggesting a role in DAT trafficking [195]. Therefore, understanding the effects of S,S-CE-158 in both males and females in animal models of PSUD will be very interesting..
- Shaikh A, Ahmad F, Teoh SL, Kumar J, Yahaya MF . Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease . Front Cell Neurosci . 17 . 1292858 . 2023 . 38026688 . 10679733 . 10.3389/fncel.2023.1292858 . free . Due to their high DAT specificity, synthetic modafinil analogs like R-modafinil, S-CE-123 (S-5-((benzhydrylsulfinyl)methyl) thiazole), S,S-CE158 (5-(((S)-((S)-(3-bromophenyl)(phenyl) methyl)sulfinyl)methyl)thiazole), and S-MK-26 ((S)-5-(((B(3- chlorophenyl)methyl)sulphinyl)methyl)thiazole) do not exert any effect on the reward pathway, making them less likely to cause addiction, abuse or withdrawal symptoms compared to the parent drug and other non-specific counterparts (Kristofova et al., 2018; Sagheddu et al., 2020; Hazani et al., 2022; Kouhnavardi et al., 2022)..
- Rotolo RA, Kalaba P, Dragacevic V, Presby RE, Neri J, Robertson E, Yang JH, Correa M, Bakulev V, Volkova NN, Pifl C, Lubec G, Salamone JD . Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding . Psychopharmacology (Berl) . 237 . 11 . 3459–3470 . November 2020 . 32770257 . 7572767 . 10.1007/s00213-020-05625-6 .
