title: The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers.
abstract: Benzodiazepines are effective short-term treatments for anxiety disorders, but their use is limited by undesirable side effects related to Central Nervous System impairment and tolerance development. SL65.1498 is a new compound that acts in vitro as a full agonist at the gamma-aminobutyric acid(A) 2 and 3 receptor and as a partial agonist at the 1 and 5 receptor subtypes. It is thought that the compound could be anxiolytic by its activation at the alpha2 and alpha3 receptor subtypes, without causing unfavourable side effects, which are believed to be mediated by the alpha1 and alpha5 subtypes. This study was a double-blind, five-way cross-over study to investigate the effects of three doses of SL65.1498 in comparison with placebo and lorazepam 2 mg in healthy volunteers. The objective was to select a dose level (expected to be therapeutically active), free of any significant deleterious effect. Psychomotor and cognitive effects were measured using a validated battery of measurements, including eye movements, body sway, memory tests, reaction-time assessments, and visual analogue scales. The highest dose of SL65.1498 showed slight effects on saccadic peak velocity and smooth pursuit performance, although to a much lesser extent than lorazepam. In contrast to lorazepam, none of the SL65.1498 doses affected body sway, visual analogue scale alertness, attention, or memory tests. This study showed that the three doses of SL65.1498 were well tolerated and induced no impairments on memory, sedation, psychomotor, and cognitive functions.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: S L
authors.initials: SL
authors.lastname: de Haas
authors.forename: K L
authors.initials: KL
authors.lastname: Franson
authors.forename: J A J
authors.initials: JA
authors.lastname: Schmitt
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
authors.forename: J B
authors.initials: JB
authors.lastname: Fau
authors.forename: C
authors.initials: C
authors.lastname: Dubruc
authors.forename: J M A
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D000328:Adult; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005133:Eye Movements / Q000187:drug effects; D005260:Female; D018755:GABA Agonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018757:GABA Modulators / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008140:Lorazepam / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D009483:Neuropsychological Tests; D004856:Postural Balance / Q000187:drug effects; D011698:Pursuit, Smooth / Q000187:drug effects; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011963:Receptors, GABA-A; D012438:Saccades / Q000187:drug effects; D055815:Young Adult
chemical_list: C432169:6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido(3,4-b)indol-1-one; D018755:GABA Agonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; D007211:Indoles; D011758:Pyrroles; D011963:Receptors, GABA-A; D008140:Lorazepam