3-Pyrazolone analogues of the 3-isoxazolol metabotropic excitatory amino acid receptor agonist homo-AMPA. Synthesis and pharmacological testing

We have previously shown that the higher homologue of (S)-glutamic acid [(S )-Glu], (S)-alpha-aminoadipic acid [(S)-alpha-AA] is selectively recognized by the mGlu(2) and mGlu(6) subtypes of the family of metabotropic glutamic acid (mGlu) receptors. Furthermore, a number of analogues of (S)-alpha-AA, in which the terminal carboxyl group has been replaced by various bioisost eric groups, such as phosphonic acid or 3-isoxazolol groups, have been show n to interact selectively with different subtypes of mGlu receptors. In thi s paper we report the synthesis of the 3-pyrazolone bioisosteres of alpha-A A, compounds (RS)-2-amino-4-(1,2-dihydro-5-methyl-3-oxo-3H-pyrazol-4-yl)but yric acid (1) and (RS)-2-amino-4-(1,2-dihydro-1,5-dimethyl-3-oxo-3H-pyrazol -4-yl)butyric acid (2). At a number of steps in the reaction sequences used , the reactions took unexpected courses and provided products which could n ot be transformed into the target compounds, and attempts to synthesize the 2,5-dimethyl isomer of 2, compound 3, failed. An X-ray crystallographic an alysis of the intermediate 1,2-dihydro-4-(2-hydroxyethyl)-2,5-dimethyl-3H-p yrazol-3-one (5b) confirmed the expected regioselectivity of the reaction b etween methylhydrazine and alpha-acetylbutyrolactone (4). Neither 1 nor 2 s howed significant effects at the different types of ionotropic glutamic aci d receptors or at mGlu(1a) (group I), mGlu(2) (group II), and mGlu(4a) and mGlu(6) (group III) receptors, representing the three indicated groups of m Glu receptors. (C) 1999 Editions scientifiques et medicales Elsevier SAS.