Article

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.

Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
Bioorganic & Medicinal Chemistry (Impact Factor: 2.9). 09/2007; 15(16):5417-23. DOI: 10.1016/j.bmc.2007.05.059
Source: PubMed

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.

0 Bookmarks
 · 
71 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Give me an H! Give me another H! The first general and highly enantioselective Ru-catalyzed transfer hydrogenation of a wide range of 1-aryl-substituted 1,2,3,4-dihydroisoquinolines is described. This atom-economic reaction proceeds under mild conditions, allowing rapid access to the corresponding biologically relevant 1-aryl-tetrahydroisoquinoline derivatives, in high yields and enantioselectivities of up to 99 %.
    Angewandte Chemie International Edition 03/2013; · 11.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Epilepsy is a common neurological disorder; however, its therapy is not satisfactory because a large number of patients suffer from refractory seizures and/or has a low quality of life due to antiepileptic drug (AED) side effects. Glutamate is the major excitatory neurotransmitter in the brain, AMPA receptors (AMPARs) represent a validated target for AEDs' development. Evidences support their role during seizures and neurodegeneration. Development of AMPAR ligands has led to two different branches of research, with the identification of competitive and noncompetitive antagonists. AREAS COVERED: We herein describe the architecture of AMPAR and the main structure-activity relationships of antagonists. Finally, we report the effects of AMPAR antagonists in preclinical models and clinical trials in epileptic patients. We reviewed the most relevant research in the field, focusing on research advances for the oldest AMPA antagonists and the new most promising molecules identified. EXPERT OPINION: Overall, the development of AMPAR antagonists confirms their great clinical potential; their arrival to clinical practice has been slowed down by their unfavorable pharmacokinetic profile and tolerability; however, their clinical use might be justified by their efficacy and the new drugs developed such as perampanel have been greatly ameliorated from both points of view.
    Expert Opinion on Investigational Drugs 07/2012; 21(9):1371-89. · 4.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A liquid chromatographic chiral stationary phase (CSP) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was applied for the first time to the resolution of biologically important 1-aryl-1,2,3,4-tetrahydroisoquinolines. The unusual resolution of cyclic secondary amino compounds on a chiral crown ether-based CSP was quite successful with the use of a mixture of methanol-acetonitrile-triethylamine at a ratio of 30/70/0.5 (v/v/v) as a mobile phase. From the chromatographic behaviours for the resolution of seven 1-aryl-1,2,3,4-tetrahydroisoquinolines, the steric bulkiness of the 1-phenyl ring at the chiral center of analytes was concluded to play an important role in the chiral recognition.
    Journal of Chromatography A 07/2011; 1218(26):4071-6. · 4.61 Impact Factor