Synthesis and anticonvulsant evaluation of N-substituted isoquinoline AMPA receptor antagonists.
In our previous studies a ligand-based approach led to the identification of noncompetitive AMPA receptor antagonists containing isoquinoline scaffold. In an attempt to perform a systematic SAR study, we synthesized new N-substituted-isoquinolines bearing the most salient features described by our 3D pharmacophore model. All compounds were screened against audiogenic seizures and some derivatives showed anticonvulsant properties. Compound 24, the most active of the series, was also tested in vitro using the patch-clamp technique and proved to antagonize AMPA-mediated effects.
Gitto
Rosaria
R
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy.
De Luca
Laura
L
Pagano
Benedetta
B
Citraro
Rita
R
De Sarro
Giovanbattista
G
Costa
Lara
L
Ciranna
Lucia
L
Chimirri
Alba
A
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D015394:Molecular Structure; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D007546:Isoquinolines; D018091:Receptors, AMPA; C039109:isoquinoline