{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T02:16:45Z","timestamp":1775009805919,"version":"3.50.1"},"reference-count":70,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2002,12,4]],"date-time":"2002-12-04T00:00:00Z","timestamp":1038960000000},"content-version":"vor","delay-in-days":33,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"the Lundbeck Foundation"},{"name":"the Danish Medical Research Council"},{"name":"the Centre for Drug Design and Transport"},{"name":"the NeuroScience PharmaBiotec Centre"},{"name":"the Danish State Biotechnology Programme"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Chemical Record"],"published-print":{"date-parts":[[2002,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The GABA<jats:sub>A<\/jats:sub> receptor system is implicated in a number of neurological and psychiatric diseases, making GABA<jats:sub>A<\/jats:sub> receptor ligands \ninteresting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on \nthe hetero\u2010pentameric GABA<jats:sub>A<\/jats:sub> receptor complex, reflecting the very strict structural requirements for GABA<jats:sub>A<\/jats:sub> receptor recognition \nand activation. Within the series of compounds showing agonist activity at the GABA<jats:sub>A<\/jats:sub> receptor site that have been developed, most of the ligands \nare structurally derived from the GABA<jats:sub>A<\/jats:sub> agonists muscimol, THIP, or isoguvacine, which we developed in the initial stages of the project. Using \nrecombinant GABA<jats:sub>A<\/jats:sub> receptors, functional selectivity was demonstrated for a number of compounds, including THIP, showing highly \nsubunit\u2010dependent potency and maximal response. In light of the interest in partial GABA<jats:sub>A<\/jats:sub> receptor agonists as potential therapeutics, \nstructure\u2013activity studies of a number of analogs of 4\u2010PIOL, a low\u2010efficacy partial GABA<jats:sub>A<\/jats:sub> agonist derived from THIP, have been \nperformed. In this connection, a series of GABA<jats:sub>A<\/jats:sub> ligands has been developed that exhibit pharmacological profiles from moderately potent \nlow\u2010efficacy partial GABA<jats:sub>A<\/jats:sub> agonist activity to potent and selective antagonist effects. Very little information is available on \ndirect\u2010acting GABA<jats:sub>A<\/jats:sub> receptor agonists in clinical studies. However, the results of clinical studies on the effect of the partial \nGABA<jats:sub>A<\/jats:sub> agonist THIP on human sleep patterns show that the functional consequences of a direct\u2010acting agonist are different from those \nseen after the administration of GABA<jats:sub>A<\/jats:sub> receptor modulators, such as benzodiazepines and barbiturates. \u00a9 2002 The Japan Chemical Journal \nForum and Wiley Periodicals, Inc., Chem Rec 2: 419\u2013430; 2002: Published online in Wiley Interscience (www.interscience.wiley.com) DOI \n10.1002\/tcr.10040<\/jats:p>","DOI":"10.1002\/tcr.10040","type":"journal-article","created":{"date-parts":[[2002,12,6]],"date-time":"2002-12-06T13:43:37Z","timestamp":1039182217000},"page":"419-430","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Specific GABA<sub>A<\/sub> agonists and partial 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