Synthesis, resolution, stereochemistry, and molecular modeling of (R)- and (S)-2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline AMPAR antagonists.
Recently we identified (R,S)-2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6) as a potent non-competitive AMPA receptor antagonist able to prevent epileptic seizures. We report here the optimized synthesis of compound 6, its resolution by chiral preparative HPLC, and the absolute configuration of (R)-enantiomer established by X-ray diffractometry. The biological tests of the single enantiomers revealed that higher anticonvulsant and antagonistic effects reside in (R)-enantiomer as also suggested by molecular modeling studies.
Gitto
Rosaria
R
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
Ficarra
Rita
R
Stancanelli
Rosanna
R
Guardo
Marta
M
De Luca
Laura
L
Barreca
Maria Letizia
ML
Pagano
Benedetta
B
Rotondo
Archimede
A
Bruno
Giuseppe
G
Russo
Emilio
E
De Sarro
Giovanbattista
G
Chimirri
Alba
A
D000818:Animals; D003292:Convulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy / Q000473:pathology; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*
C470657:2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D044005:Tetrahydroisoquinolines