title: The effects of a glycine reuptake inhibitor R231857 on the central nervous system and on scopolamine-induced impairments in cognitive and psychomotor function in healthy subjects.
abstract: The effects of the selective inhibitor of the glycine transporter 1, R231857, in development for schizophrenia, on the central nervous system (CNS) were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, four-period crossover ascending dose study. Pharmacokinetics, body sway, saccadic and smooth pursuit eye movements, pupillometry, pharmacoelectroencephalogram (EEG), Visual Analogue Scales (VAS) for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Stroop test, Visual and Verbal Learning Task (VVLT) and hormone levels were assessed. R231857 was administered alone and together with scopolamine to investigate the potential reversal of anticholinergic CNS impairment by the glycine reuptake inhibitor. Forty-two of the 45 included subjects completed the study. Scopolamine significantly affected almost every CNS parameter measured in this study. R231857 alone showed some pharmacodynamic changes compared with placebo. Although these effects might be an indication that R231857 penetrated the CNS, they were not consistent or dose-related. R231857 had some small effects on scopolamine-induced CNS-impairment, which were also not clearly dependent on dose. Scopolamine proved to be an accurate, reproducible and safe model to induce CNS impairment by an anticholinergic mechanism. R231857 lacked consistent dose-related effects in this study, probably because CNS concentrations were too low to produce significant/ reproducible CNS-effects or to affect the scopolamine challenge in healthy volunteers. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.
authors: Centre for Human Drug Research, Leiden, The Netherlands. mmoolenaar@chdr.nl
authors: M
authors: M
authors: Liem-Moolenaar
authors: R W M
authors: RW
authors: Zoethout
authors: P
authors: P
authors: de Boer
authors: M
authors: M
authors: Schmidt
authors: M L
authors: ML
authors: de Kam
authors: A F
authors: AF
authors: Cohen
authors: K L
authors: KL
authors: Franson
authors: J M A
authors: JM
authors: van Gerven
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects; D001288:Attention / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D005663:Furans / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011596:Psychomotor Disorders / Q000139:chemically induced*; D011597:Psychomotor Performance / Q000187:drug effects; D011698:Pursuit, Smooth / Q000187:drug effects; D018009:Receptors, Glycine / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*; D012601:Scopolamine / Q000494:pharmacology*; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D005663:Furans; D050487:Glycine Plasma Membrane Transport Proteins; C556129:R231857; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C493268:SLC6A9 protein, human; D013876:Thiophenes; D012601:Scopolamine