title: Characterization of pharmacological and wake-promoting properties of the dopaminergic stimulant sydnocarb in rats.
abstract: Sydnocarb is a psychomotor stimulant structurally similar to d-amphetamine (D-AMPH) and is used in Russia for the treatment of a variety of neuropsychiatric comorbidities. The nature of sydnocarb-induced facilitation of dopamine (DA) neurotransmission [DA release versus DA transporter (DAT) inhibition] is not clear. The present study characterized the pharmacological actions and behavioral effects of intraperitoneal sydnocarb in male Sprague-Dawley rats. Where relevant, comparisons were made with intraperitoneal D-AMPH. Unlike D-AMPH, which causes release of DA from rat synaptosomes (EC(50) = 0.10 μM; 95% confidence limits, 0.06-0.18), sydnocarb (up to 100 μM) did not. Sydnocarb potently (K(i) = 8.3 ± 0.7 nM) blocked recombinant human DAT expressed in Chinese hamster ovary-K1 cells and less potently blocked the norepinephrine transporter (K(i) = 10.1 ± 1.5 μM). Sydnocarb at 10 μM did not bind to 64 other targets. In rats, 10 and 30 mg/kg sydnocarb showed a 2-fold longer half-life in plasma and brain and a 5-fold lower brain-to-plasma ratio compared with 0.3 and 1 mg/kg D-AMPH. In the Irwin assay, sydnocarb was well tolerated up to 30 mg/kg; D-AMPH-like stereotypic behaviors were evident at 100 mg/kg. Behavioral effects of 30 mg/kg sydnocarb and 0.3 mg/kg D-AMPH were comparable. In a sleep/wake assay, 10 mg/kg sydnocarb and 1 mg/kg D-AMPH increased wakefulness comparably; however, sydnocarb (up to 30 mg/kg) did not induce D-AMPH-like rebound hypersomnolence (RHS). Like D-AMPH, sydnocarb enhanced theta power, an electrophysiological measure of cognitive function. In conclusion, sydnocarb is a selective and potent DAT inhibitor that produces robust increases in the wake state without RHS, and with potential cognitive-enhancing properties.
authors.affiliation: CNS Biology, Worldwide Discovery Research, Cephalon, Inc., West Chester, Pennsylvania, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: Dorothy G
authors.initials: DG
authors.lastname: Flood
authors.forename: Maciej
authors.initials: M
authors.lastname: Gasior
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology*; D004569:Electroencephalography; D004576:Electromyography; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D013558:Sydnones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013826:Theta Rhythm / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D007473:Ion Channels; D018377:Neurotransmitter Agents; D013558:Sydnones; D003913:Dextroamphetamine; C009257:sidnocarb; D004298:Dopamine