Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects.
Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced gamma-aminobutyric acid-mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.
Rupprecht
Rainer
R
Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstrasse 7, Munich 80336, Germany. rainer.rupprecht@med.uni-muenchen.de
Rammes
Gerhard
G
Eser
Daniela
D
Baghai
Thomas C
TC
Schüle
Cornelius
C
Nothdurfter
Caroline
C
Troxler
Thomas
T
Gentsch
Conrad
C
Kalkman
Hans O
HO
Chaperon
Frederique
F
Uzunov
Veska
V
McAllister
Kevin H
KH
Bertaina-Anglade
Valerie
V
La Rochelle
Christophe Drieu
CD
Tuerck
Dietrich
D
Floesser
Annette
A
Kiese
Beate
B
Schumacher
Michael
M
Landgraf
Rainer
R
Holsboer
Florian
F
Kucher
Klaus
K
D000328:Adult; D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000378:metabolism*; D001569:Benzodiazepines / Q000009:adverse effects; D002460:Cell Line; D004361:Drug Tolerance; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism; D016584:Panic Disorder / Q000188:drug therapy; D011687:Purines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control; D013758:Tetragastrin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D014151:Anti-Anxiety Agents; D007546:Isoquinolines; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D018377:Neurotransmitter Agents; D011687:Purines; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C499229:TSPO protein, human; D013758:Tetragastrin; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; C037850:PK 11195; D000525:Alprazolam