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 (IC50 = 35 μM), over the 5-n-propyl analogue (5c), which was a selective mGluR2 agonist (EC50 = 72 μM), to the 5-cyclohexylmethyl analogue (5g), which was a selective mGluR2 antagonist (Ki = 32 μM), and the 5-phenylethyl analogue (5j), which was a weak but apparently selective mGluR1 antagonist (Ki = 230 μM). 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. © 2007 Elsevier Ltd. All rights reserved.