| Abstract
| - Regioisomeric 3-carboxyisoxazolinyl prolines [CIP-A (±)-6 and CIP-B (±)-7] and 3-hydroxyisoxazolinyl prolines [(±)-8 and (±)-9] were synthesized and assayed for glutamate receptoractivity. The tests were carried out in vitro by means of receptor binding techniques, secondmessenger assays, and the rat cortical wedge preparation. CIP-A showed a good affinity forboth 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and kainic acid (KAIN)receptors. These results were confirmed in the cortical slice model where CIP-A displayed anEC50 value very close to that of AMPA. The convulsant properties of all the compounds wereevaluated in vivo on DBA/2 mice after icv injection. CIP-A showed a convulsant activity,measured as tonus and clonus seizures, 18−65 times higher than that produced by AMPA. Itwas also quite active after ip administration, since it induced seizures in mice at doses as lowas 3.2 nmol/mouse. On the basis of the above-reported results we prepared and tested theenantiomers of CIP-A and CIP-B, obtained by reacting (S)-3,4-didehydroproline and (R)-3,4-didehydroproline, respectively, with ethoxycarbonylformonitrile oxide. In all the tests theS-form, CIP-AS [(−)-6], emerged as the eutomer evidencing common stereochemical requirements with the reference compounds AMPA and KAIN. Through modeling studies, carriedout on CIP-A, AMPA, and KAIN, active conformations for CIP-AS and AMPA at AMPA receptorsas well as for CIP-AS and KAIN at KAIN receptors are suggested.
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