Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side effects associated with baclofen or benzodiazepines.
The role of GABAB receptors in various behavioral processes has been largely defined using the prototypical GABAB receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioral paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety, the role of GABAB receptors in these disorders is largely unclear. We recently identified GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) as a selective allosteric positive modulator at GABAB receptors. The aim of the present study was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition, and anxiety. The following tests were included: locomotor activity in rats and mice, rotarod and traction tests (including determinations of core temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital- and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature, or narcosis. Most interestingly, GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABAB receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side effect profile to both baclofen and benzodiazepines.
Cryan
John F
JF
Psychiatry Program, Neuroscience Research, The Novartis Institutes for BioMedical Research WSJ 386.344, Novartis Pharma AG, Basel CH-4002, Switzerland. john_f.cryan@pharma.novartis.com
Kelly
Peter H
PH
Chaperon
Frederique
F
Gentsch
Conrad
C
Mombereau
Cedric
C
Lingenhoehl
Kurt
K
Froestl
Wolfgang
W
Bettler
Bernhard
B
Kaupmann
Klemens
K
Spooren
Will P J M
WP
D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001418:Baclofen / Q000009:adverse effects; D001569:Benzodiazepines / Q000009:adverse effects; D001831:Body Temperature / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D004338:Drug Combinations; D005334:Fever / Q000209:etiology; D018755:GABA Agonists / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism; D045442:Rotarod Performance Test; D013312:Stress, Physiological / Q000150:complications; D013997:Time Factors; D014143:Traction
D014151:Anti-Anxiety Agents; D003517:Cyclopentanes; D004338:Drug Combinations; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D011743:Pyrimidines; D018080:Receptors, GABA-B; D001569:Benzodiazepines; D001418:Baclofen