Low-Affinity/High-Selectivity Dopamine Transport Inhibition Sufficient to Rescue Cognitive Functions in the Aging Rat

Abstract

The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory. Following binding studies to DAT, NET and SERT, GPCR and kinome screening, pharmacokinetics and a basic neurotoxic screen, S-CE-123 was tested for its potential to enhance and/or rescue cognitive functions in young and in aged rats in the non-invasive reward-motivated paradigm of a hole-board test for spatial learning. In addition, an open field study with young rats was carried out. We demonstrated that S-CE-123 is a low-affinity but highly selective dopamine reuptake inhibitor with good bioavailability. S-CE-123 did not induce hyperlocomotion or anxiogenic or stereotypic behaviour in young rats. Our compound improved the performance of aged but not young rats in a reward-motivated task. The well-described impairment of the dopaminergic system in aging may underlie the age-specific effect. We propose S-CE-123 as a possible candidate for developing a tentative therapeutic strategy for age-related cognitive decline and cognitive dysfunction in psychiatric disorders.

Process Development and Scale-Up of a Novel Atypical DAT Inhibitor (S)-CE-123

“…In the US, programs have been conducted to develop potential pharmacotherapies, which have led to the identification of a promising lead molecule, JJC8-091, that exhibits a novel binding mode at DAT . JJC8-091, ( S )-CE-123, and R - and S -modafinil exert a unique binding profile to DAT that is clearly distinguished from the binding of cocaine and thus exert a pharmacological profile of atypical DAT inhibitors. ,, …”

“…13,14 (S)-CE-123 belongs to a class of atypical DAT inhibitors, with a pharmacological profile that can be clearly distinguished from those of cocaine and amphetamine. 10 Atypical DAT inhibitors are being extensively tested and strong efforts are being made to develop them as therapeutics for treatment of drug addiction. 15−19 The necessity of bringing in drugs against addiction is also reflected by the number of deaths of young and middle-aged adults in the US and Canada due to the current opioid crisis: 15.8 and 6.4 per 100,000 people in 2019, respectively.…”

“…15 JJC8-091, (S)-CE-123, and R-and S-modafinil exert a unique binding profile to DAT that is clearly distinguished from the binding of cocaine and thus exert a pharmacological profile of atypical DAT inhibitors. 10,15,21 For initial pharmacological profiling, (S)-CE-123 was produced in house via separations on a chiral phase, which was later on replaced by total synthesis on a small scale with the enantioselective oxidation of sulfide to a sulfoxide moiety in the last step. 12 For enantioselective catalysis of the oxidation of sulfides, Modena and co-workers investigated several complexes comprising a metal and a chiral tartrate, finding out that a species made of titanium(IV) tetraisopropoxide (TTIP) with the formula Ti{OCH(CH 3 ) 2 } 4 and (R,R)-diethyl tartrate in a 1 to 4 molar ratio provided high enantioselectivity.…”

“…( S )-5-((Benzhydrylsulfinyl)­methyl)­thiazole, ( S )-CE-123, is a novel modafinil analogue (Figure ) with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. − Substantial chemical modifications of modafinil over the years have led to the discovery of ( S )-CE-123, but the structure–activity relationship (SAR) studies clearly indicated the necessity of preserving a sulfoxide moiety within the core structure for obtaining an active moiety. , ( S )-CE-123 belongs to a class of atypical DAT inhibitors, with a pharmacological profile that can be clearly distinguished from those of cocaine and amphetamine …”

“… 13 , 14 ( S )-CE-123 belongs to a class of atypical DAT inhibitors, with a pharmacological profile that can be clearly distinguished from those of cocaine and amphetamine. 10 …”