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Reduced side effect liability of novel β‐subunit selective GABA A receptor allosteric modulators
Author(s) -
Yoshimura Ryan F,
Tran Minhtam B,
Hogenkamp Derk J,
Johnstone Timothy B,
Gee Kelvin W
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb463
Subject(s) - allosteric regulation , anxiolytic , pharmacology , agonist , gabaa receptor , benzodiazepine , sedative , diazepam , chemistry , allosteric modulator , sedation , flumazenil , receptor , medicine
Current benzodiazepine (BZ) anxiolytics, including diazepam, have well‐known side effects including sedation, memory impairment, abuse‐liability, withdrawal and limited tolerance (Kaplan and DuPont, 2005). We have previously characterized β‐subunit selective GABA A receptor (GABA A Rs) positive allosteric modulators (PAMs) as anxiolytics with a reduced sedative liability (Gee et al. , 2010). Additional testing of the prototypical compound, UCI2‐261, a GABA A R β‐subunit selective anxiolytic, in a number of behavioral models reveal differences between it and typical agonist BZs. Unlike diazepam (2.5 mg/kg i.p.), UCI2‐261 (100 mg/kg, i.p.) does not have a significant amnestic effect in adult, male Sprague‐Dawley rats as measured by the eight‐arm radial arm maze. Furthermore, subchronic (7 days, q.d.) treatment of adult, male CD‐1 mice with UCI2‐261 (10 mg/kg, i.p.) does not induce tolerance to its anxiolytic effect in the elevated plus maze. These results suggest that β‐subunit selective GABA A R PAMs not only have reduced sedative‐liability, but may not share other side effects commonly associated with agonist BZs.