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 -