4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes.
4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies, and the series of 4-alkyl-HIBO analogues have been extended in this paper in the search for versatile agents. Pharmacological characterization of five new analogues, branched and unbranched 4-alkyl-HIBO analogues, have been carried out. The present compounds are all weak antagonists at Group I mGluRs (mGluR1 and 5) presenting only small differences in potencies (Ki values ranging from 89 to 670 microM). Affinities were studied at native and cloned iGluRs, and the compounds described show preference for the AMPA receptor subtypes GluR1 and 2 over GluR3 and 4. However, compared to previous 4-alkyl-HIBO analogues, these compounds show a remarkably high affinity for the Kain preferring subtype GluR5. The observed GluR5 affinities were either similar or higher compared to their GluR1 and 2 affinity. Isopropyl-HIBO showed the highest affinity for GluR5 (Ki=0.16 microM), and represents a unique compound with high affinity towards the three subtypes GluR1, 2 and 5. In general, these compounds represent new selectivity profiles compared to previously reported Glu receptor analogues.
Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark. um@dfuni.dk
Ulf
U
Madsen
Darryl S
DS
Pickering
Birgitte
B
Nielsen
Hans
H
Bräuner-Osborne
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007313:Insecta; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000493:pharmacokinetics
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D021122:Protein Subunits; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D014316:Tritium; D007051:Ibotenic Acid; C023364:homoibotenic acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid