title: Novel 5-substituted 1-pyrazolol analogues of ibotenic acid: synthesis and pharmacology at glutamate receptors.
abstract: 5-Substituted 1-pyrazolol analogues of ibotenic acid have been synthesized and pharmacologically characterized on ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs). The syntheses involved introduction of bromide, alkyls, phenyl and arylalkyls in the 5-position of 1-benzyloxypyrazole leading to 5-substituted (RS)-2-amino-(1-hydroxy-4-pyrazolyl)acetic acids (5a-l). The pharmacological activities of the synthesized analogues ranged from the 5-cyclopropylmethyl analogue (5f) with weak but selective affinity for NMDA receptors (IC(50)=35 microM), over the 5-n-propyl analogue (5c), which was a selective mGluR2 agonist (EC(50)=72 microM), to the 5-cyclohexylmethyl analogue (5g), which was a selective mGluR2 antagonist (K(i)=32 microM), and the 5-phenylethyl analogue (5j), which was a weak but apparently selective mGluR1 antagonist (K(i)=230 microM). This series of compounds afforded GluR ligands with a broad spectrum of pharmacological profiles, and showing potential for development of new compounds with subtype-selective activities at various GluRs.
authors: The Danish University of Pharmaceutical Sciences, Department of Medicinal Chemistry, 2100 Copenhagen, Denmark.
authors: Charlotte G
authors: CG
authors: Jørgensen
authors: Hans
authors: H
authors: Bräuner-Osborne
authors: Birgitte
authors: B
authors: Nielsen
authors: Jan
authors: J
authors: Kehler
authors: Rasmus P
authors: RP
authors: Clausen
authors: Povl
authors: P
authors: Krogsgaard-Larsen
authors: Ulf
authors: U
authors: Madsen
mesh_terms: D000478:Alkylation; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D018690:Excitatory Amino Acid Agonists; D007051:Ibotenic Acid; D007202:Indicators and Reagents; D011720:Pyrazoles; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104722:glutamate receptor ionotropic, AMPA 2