Synthesis and enantiopharmacology of new AMPA-kainate receptor agonists
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Synthesis and enantiopharmacology of new AMPA-kainate receptor agonists. / Conti, P; De Amici, M; De Sarro, G; Rizzo, M; Stensbøl, T B; Bräuner-Osborne, Hans; Madsen, U; Toma, L; De Micheli, C.
In: Journal of Medicinal Chemistry, Vol. 42, No. 20, 07.10.1999, p. 4099-107.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Synthesis and enantiopharmacology of new AMPA-kainate receptor agonists
AU - Conti, P
AU - De Amici, M
AU - De Sarro, G
AU - Rizzo, M
AU - Stensbøl, T B
AU - Bräuner-Osborne, Hans
AU - Madsen, U
AU - Toma, L
AU - De Micheli, C
PY - 1999/10/7
Y1 - 1999/10/7
N2 - 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 EC(50) 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.
AB - 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 EC(50) 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.
KW - Animals
KW - Cerebral Cortex
KW - Convulsants
KW - Excitatory Amino Acid Agonists
KW - Isoxazoles
KW - Male
KW - Mice
KW - Mice, Inbred DBA
KW - Models, Molecular
KW - Molecular Conformation
KW - Proline
KW - Pyrroles
KW - Radioligand Assay
KW - Rats
KW - Receptors, AMPA
KW - Receptors, Kainic Acid
KW - Stereoisomerism
M3 - Journal article
C2 - 10514280
VL - 42
SP - 4099
EP - 4107
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 20
ER -
ID: 45596236