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.[2][3][5]
 | |
| Clinical data | |
|---|---|
| Other names | (S,S)-CE-158; S,S-CE-158 |
| Drug class | Atypical dopamine reuptake inhibitor |
| Identifiers | |
| |
| PubChem CID | |
| Chemical and physical data | |
| Formula | C17H14BrNOS2 |
| Molar mass | 392.33 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
CE-158 is a highly selective DRI with much greater potency than modafinil.[3][5] As (S,S)-CE-158, its inhibitory potencies (IC50) at the monoamine transporters are 227 nM at the dopamine transporter (DAT), 11,970 nM at the norepinephrine transporter (NET) (53-fold lower), and inactive at the serotonin transporter (SERT).[5]
The drug shows pro-motivational effects in animals and reverses tetrabenazine-induced motivational deficits.[1] 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.[3][2][5]
CE-158 was first described by 2020.[5] It is closely related to CE-123, an earlier modafinil analogue.[4][5] CE-158 and related agents are of interest in the potential treatment of motivational disorders, psychostimulant use disorder (PSUD), and Alzheimer's disease.[1][2][3][4][5]
See also
editReferences
edit- ^ a b c Salamone JD, Correa M (January 2024). "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. doi:10.1146/annurev-psych-020223-012208. hdl:10234/207207. PMID 37788571.
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).
- ^ a b c d Treadway MT, Salamone JD (2022). "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 58. Cham: 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 [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.
- ^ a b c d e Hersey M, Bartole MK, Jones CS, Newman AH, Tanda G (July 2023). "Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors". Molecules. 28 (13): 5270. doi:10.3390/molecules28135270. PMC 10343811. PMID 37446929.
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.
- ^ a b c Shaikh A, Ahmad F, Teoh SL, Kumar J, Yahaya MF (2023). "Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease". Front Cell Neurosci. 17: 1292858. doi:10.3389/fncel.2023.1292858. PMC 10679733. PMID 38026688.
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).
- ^ a b c d e f g h Rotolo RA, Kalaba P, Dragacevic V, Presby RE, Neri J, Robertson E, et al. (November 2020). "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. doi:10.1007/s00213-020-05625-6. PMC 7572767. PMID 32770257.