Synthesis and Enantiopharmacology of New AMPA-Kainate Receptor Agonists

• Published in: Journal of medicinal chemistry Vol. 42; no. 20; pp. 4099 - 4107
• Main Authors: Conti, Paola, De Amici, Marco, De Sarro, Giovambattista, Rizzo, Milena, Stensbøl, Tine Bryan, Bräuner-Osborne, Hans, Madsen, Ulf, Toma, Lucio, De Micheli, Carlo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.10.1999; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Cerebral Cortex - metabolism; Chemistry, Medicinal; Convulsants - chemical synthesis; Convulsants - chemistry; Convulsants - metabolism; Convulsants - pharmacology; Excitatory Amino Acid Agonists - chemical synthesis; Excitatory Amino Acid Agonists - chemistry; Excitatory Amino Acid Agonists - metabolism; Excitatory Amino Acid Agonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); In Vitro Techniques; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - metabolism; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Mice, Inbred DBA; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Proline - analogs & derivatives; Proline - chemical synthesis; Proline - chemistry; Proline - metabolism; Proline - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - metabolism; Pyrroles - pharmacology; Radioligand Assay; Rats; Receptors, AMPA - agonists; Receptors, Kainic Acid - agonists; Science & Technology; Stereoisomerism; CHANNEL; ANALOGS; AFFINITY; METABOTROPIC GLUTAMATE RECEPTORS; IBOTENIC ACID; ANTAGONISTS; AMINO-ACID NEUROTRANSMISSION; BINDING; MODULATION; METHYL-D-ASPARTATE; Agonist; Rat; Rodentia; Glutamate receptor; In vitro; Biological activity; Kainate receptor; In vivo; α-Aminoacid; Vertebrata; AMPA receptor; Mammalia; Mouse; Animal; Enantiomer; Bicyclic compound; S configuration; Chemical synthesis; Conformation; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991081g

Regioisomeric 3-carboxyisoxazolinyl prolines [CIP-A (±)-6 and CIP-B (±)-7] and 3-hydroxyisoxazolinyl prolines [(±)-8 and (±)-9] were synthesized and assayed for glutamate receptor activity. The tests were carried out in vitro by means of receptor binding techniques, second messenger assays, and the rat cortical wedge preparation. CIP-A showed a good affinity for both 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 an EC50 value very close to that of AMPA. The convulsant properties of all the compounds were evaluated 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. It was also quite active after ip administration, since it induced seizures in mice at doses as low as 3.2 nmol/mouse. On the basis of the above-reported results we prepared and tested the enantiomers 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 the S-form, CIP-AS [(−)-6], emerged as the eutomer evidencing common stereochemical requirements with the reference compounds AMPA and KAIN. Through modeling studies, carried out on CIP-A, AMPA, and KAIN, active conformations for CIP-AS and AMPA at AMPA receptors as well as for CIP-AS and KAIN at KAIN receptors are suggested.