title: 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.
abstract: 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Rita
authors.initials: R
authors.lastname: Ficarra
authors.forename: Rosanna
authors.initials: R
authors.lastname: Stancanelli
authors.forename: Marta
authors.initials: M
authors.lastname: Guardo
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Benedetta
authors.initials: B
authors.lastname: Pagano
authors.forename: Archimede
authors.initials: A
authors.lastname: Rotondo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bruno
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.forename: Giovanbattista
authors.initials: G
authors.lastname: De Sarro
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: 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*
chemical_list: 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