CE-158

CE-158, most active as its (S,S) stereoisomer, is a thiazole-bearing analogue in the same modafinil-derived series that produced the earlier compound CE-123. It was designed as a slow-dissociating, highly selective dopamine transporter (DAT) inhibitor. The foundational report described its synthesis and pharmacology and showed that (S,S)-CE-158 increases dopamine in cognition-related brain regions, restores dendritic spine density in the dorsal hippocampus of aging rats, improves behavioral flexibility in scopolamine-compromised animals, and reinstates learning and memory recall in aged rats to a level comparable with young controls.

A follow-up behavioral, electrophysiological, and microdialysis study confirmed that CE-158 dose-dependently potentiates dopamine neurotransmission in the medial prefrontal cortex, increases the number and firing of active pyramidal neurons, and stimulates exploratory behavior, while chronic dosing did not produce locomotor sensitization, sensorimotor gating deficits, or working-memory impairment, an encouraging preclinical safety signal for a dopaminergic agent.

More recent transporter-kinetics work established that the slow off-rate, meaning extended residence time at DAT, is what drives the robust cognitive benefit; among a panel of R-modafinil analogues, long-residence compounds such as (S,S)-CE-158 and S-MK-26 produced the strongest gains in cognitive flexibility. This series traces directly to the parent modafinil analogue CE-123, which itself improved memory acquisition and retrieval in rats through DAT blockade and downstream dopamine D1 receptor engagement. CE-158 remains a laboratory tool compound; there are no clinical trials, no approved use, and no established human dosing.

Human safety is unknown; no clinical studies have been conducted. In rodents, chronic administration at 1 and 10 mg/kg was well tolerated and did not induce locomotor sensitization, disrupt prepulse inhibition, or impair working memory, which are behaviors used to flag abuse potential and pro-psychotic risk. As with any dopaminergic reuptake inhibitor, translational abuse-liability and cardiovascular questions remain open until human data exist. It should be regarded as an experimental substance not intended for human consumption.

CE-158 arose from a University of Vienna, Paracelsus Medical University Salzburg, and University of Cagliari collaboration seeking safer dopamine-based cognitive enhancers built on the modafinil scaffold. Its 2021 characterization in Molecular Psychiatry framed it as a candidate for age-related cognitive decline, and subsequent studies refined the link between DAT binding kinetics and cognitive benefit.

Within nootropic and neuropharmacology circles CE-158 is discussed as a promising next-generation, low-liability dopaminergic cognitive enhancer and as a proof of concept that slow transporter dissociation can separate pro-cognitive effects from stimulant abuse potential. It is not commercially available and remains preclinical.