CE-158

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]

Other names(S,S)-CE-158; S,S-CE-158

Drug classAtypical dopamine reuptake inhibitor

CAS Number

2621388-55-2^Y

PubChem CID

156150588

Quick facts Clinical data, Other names ...

CE-158
Clinical data

Other names	(S,S)-CE-158; S,S-CE-158
Drug class	Atypical dopamine reuptake inhibitor
Identifiers
IUPAC name 5-(3-bromophenyl)-phenylmethyl sulfinylmethyl-1,3-thiazole
CAS Number	2621388-55-2^Y
PubChem CID	156150588
Chemical and physical data
Formula	C₁₇H₁₄BrNOS₂
Molar mass	392.33 gÂ·mol^â1
3D model (JSmol)	Interactive image
SMILES C1=CC=C(C=C1)C(C2=CC(=CC=C2)Br)S(=O)CC3=CN=CS3
InChI InChI=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 Key:KWWHBBCVAQTAFQ-UHFFFAOYSA-N

CE-158 is a highly selective DRI with much greater potency than modafinil.^[3]^[5] As (S,S)-CE-158, its inhibitory potencies (IC₅₀Tooltip half-maximal inhibitory concentration) 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]

References

[1]
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): 1â32. 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).
[2]
Treadway MT, Salamone JD (2022). "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Anhedonia: Preclinical, Translational, and Clinical Integration. Current Topics in Behavioral Neurosciences. Vol. 58. Cham. pp. 325â353. 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.{{cite book}}: CS1 maint: location missing publisher (link)
[3]
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.
[4]
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).
[5]
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): 3459â3470. doi:10.1007/s00213-020-05625-6. PMC 7572767. PMID 32770257.

See also

References

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