title: 5-Substituted imidazole-4-acetic acid analogues: synthesis, modeling, and pharmacological characterization of a series of novel gamma-aminobutyric acid(C) receptor agonists.
abstract: A series of ring-substituted analogues of imidazole-4-acetic acid (IAA, 4), a partial agonist at both GABAA and GABAC receptors (GABA = gamma-aminobutyric acid), have been synthesized. The synthesized compounds 8a-l have been evaluated as ligands for the alpha1beta2gamma2S GABAA receptors and the rho1 GABAC receptors using the FLIPR membrane potential (FMP) assay and by electrophysiology techniques. None of the tested compounds displayed activity at the GABAA receptors at concentrations up to 1000 microM. However, the 5-Me, 5-Ph, 5-p-Me-Ph, and 5-p-F-Ph IAA analogues, 8a,c,f,g, displayed full agonist activities at the rho1 receptors in the FMP assay (EC50 in the range 22-420 microM). Ligand-protein docking identified the Thr129 in the alpha1 subunit and the corresponding Ser168 residue in rho1 as determinants of the selectivity displayed by the 5-substituted IAA analogues. The fact that GABA, 4, and 8a displayed decreased agonist potencies at a rho1Ser168Thr mutant compared to the WT rho1 receptor strongly supported this hypothesis. However, in contrast to GABA and 4, which exhibited increased agonist potencies at a alpha1(Thr129Ser)beta2gamma2 mutant compared to WT GABAA receptor, the data obtained for 8a at the WT and mutant receptors were nonconclusive.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Madsen
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Uffe
authors.initials: U
authors.lastname: Kristiansen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Camilla P
authors.initials: CP
authors.lastname: Hansen
authors.forename: Mogens
authors.initials: M
authors.lastname: Larsen
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000819:agonists / Q000235:genetics / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; C087200:GABA-C receptor; D007093:Imidazoles; D008024:Ligands; D021122:Protein Subunits; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C005954:imidazoleacetic acid