TY - JOUR
T1 - GABA A agonists and partial agonists
T2 - THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic
AU - Krogsgaard-Larsen, Povl
AU - Frølund, Bente
AU - Liljefors, Tommy
AU - Ebert, Bjarke
PY - 2004/10/15
Y1 - 2004/10/15
N2 - The GABA A receptor system is implicated in a number of central nervous system (CNS) disorders, making GABA A receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABA A receptor complex, reflecting the very strict structural requirements for GABA A receptor recognition and activation. A large number of the compounds showing agonist activity at the GABA A receptor site are structurally derived from the GABA A agonists muscimol, THIP (Gaboxadol), or isoguvacine, which we developed at the initial stage of the project. Using recombinant GABA A receptors, functional selectivity has been shown for a number of compounds, including THIP, showing subunit-dependent potency and maximal response. The pharmacological and clinical activities of THIP probably reflect its potent effects at extrasynaptic GABA A receptors insensitive to benzodiazepines and containing α 4β 3δ subunits. The results of ongoing clinical studies on the effect of the partial GABA A agonist THIP on human sleep pattern show that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA A receptor modulators, such as benzodiazepines. In the light of the interest in partial GABA A receptor agonists as potential therapeutics, structure-activity studies of a number of analogues of 4-PIOL, a low-efficacy partial GABA A agonist derived from THIP, have been performed. In this connection, a series of GABA A ligands has been developed showing pharmacological profiles ranging from low-efficacy partial GABA A agonist activity to selective antagonist effect.
AB - The GABA A receptor system is implicated in a number of central nervous system (CNS) disorders, making GABA A receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABA A receptor complex, reflecting the very strict structural requirements for GABA A receptor recognition and activation. A large number of the compounds showing agonist activity at the GABA A receptor site are structurally derived from the GABA A agonists muscimol, THIP (Gaboxadol), or isoguvacine, which we developed at the initial stage of the project. Using recombinant GABA A receptors, functional selectivity has been shown for a number of compounds, including THIP, showing subunit-dependent potency and maximal response. The pharmacological and clinical activities of THIP probably reflect its potent effects at extrasynaptic GABA A receptors insensitive to benzodiazepines and containing α 4β 3δ subunits. The results of ongoing clinical studies on the effect of the partial GABA A agonist THIP on human sleep pattern show that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA A receptor modulators, such as benzodiazepines. In the light of the interest in partial GABA A receptor agonists as potential therapeutics, structure-activity studies of a number of analogues of 4-PIOL, a low-efficacy partial GABA A agonist derived from THIP, have been performed. In this connection, a series of GABA A ligands has been developed showing pharmacological profiles ranging from low-efficacy partial GABA A agonist activity to selective antagonist effect.
KW - 4-PIOL
KW - Agonist
KW - Clinical studies
KW - Functional selectivity
KW - GABA receptor
KW - Muscimol
KW - Non-opioid analgesia
KW - Novel hypnotic effects
KW - Partial agonist
KW - THIP (Gaboxadol)
UR - http://www.scopus.com/inward/record.url?scp=4644268516&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2004.06.040
DO - 10.1016/j.bcp.2004.06.040
M3 - Journal article
C2 - 15451401
AN - SCOPUS:4644268516
VL - 68
SP - 1573
EP - 1580
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 8
ER -