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The Pharmaceutical Society of Korea (대한약학회)
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Synthesis and anticonvulsant evaluation of a series of (R)-and (S)-N-Cbz-.alpha.-aminosuccinmide and their structure activity relationship

  • Published : 1996.08.01
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Abstract

A series of N-Cbz${alpha}$-aminosucinimides (1), combining common moieties of various anticonvulsants such as N-CO-C-N and cyclic imide in a single molecule, were synthesized from the corresponding (R)- and (S)-N-Cbz-aspartic acid (2). And their in vivo anticonvulsant evaluations in MES and PTZ test were investigated. And also the rotorod test for neurotoxicity was investigated. All the tested compounds (1), except 1c and 1f, showed significant anticonvulsant activities in both MES and PTZ test. And the most active compound among them in MES test was (R)-N-Cbz-${alpha}$-amino-N-methylsuccinimide (1b) $(ED_50/=52.5 mg/kg)$ and (S)-N-Cbz-aminosuccinimide((1d) was most active in PTZ test $(ED_50/=78.1 mg/kg)$. And the $TD_50$ values of the tested compounds were above 117.5 mg/kg. These pharmacological data were comparable to those of currently available anticonvulsants. And also we found that the pharmacological effects were dependent on their N-substituted alkyl chains and their stereochemistry.

Keywords

References

  1. J. Med. Chem. v.36 The Synthesis of Novel GABA Uptake Inhibitors. 1. Elucidation of the Structure-Activity Studies Leading to the Choice of (R)-1-[4,4-Bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an Anticonvulsant Drug Candidate Andersen,K.E.;Braestrup,C.B.;Gronvald,F.C.;Jorgensen,A.S.;Nielsen,E.B.;Sonnewald,U.;Sorensen,P.O.;Suzdak,P.D.;Knutsen,L.J.S.
  2. J. Pharm. Sci. v.76 Anticonvulsant Activity of Indanylspirosuccinimide Mannich Bases Bornstein,M.R.;Doukas,P.H.
  3. J. Med. Chem. v.37 Bicycloc Hydantoins with a Bridgehead Nitrogen, Comparison of Anticonvulsant Activities with Binding to the Neuronal Voltage-Dependent Sodium Channel Brouillette,W.J.;Jestkov,V.P.;Brown,M.L.;Akhatar,M.S.;DeLrey,T.M.;Brown,G.B.
  4. Lippincott's illustrated Reviews : Pharmacology Harvey,R.A.;Champe,P.C.
  5. J. Pharm. Sci. v.83 Substituted 2-Ben-zothiazolamines as Sodium Flux Inhibitors: Quantitative Structure-Activity Relationships and Anticonvulsant Activity Hays,S.J.;Rice,M.J.;Ortwine,D.F.;Johnson,G.;Schwarz,R.D.;Boyd,D.K.;Coperando,L.F.;Vartanian,M.G.;Boxer,P.A.
  6. J. Med. Chem. v.36 Synthesis and Binding Properties of 2-Amino-5-phosphono-3-pentenoic acid Photoaffinty Ligands as Probes for the Glutamate Recognition Site of the NMDA Recptor Heckendorn,R.;Allgeier,H.;Baud,J.;Gundenhauser,W.;Angst,C.
  7. Chem. Pharm. Bull. v.17 Peptide. I. Selective protection of α- or Side chain Carboxyl Groups of Aspartic and Glutamic Acid. A Facile Synthesis of β-Aspartyl and γ-Glutamyl Peptides Itoh,M.
  8. J. Pharm. Sci. v.83 Anticonvulsant Properties of N-substituted α,α-Diamino acid Derivatives Kohn,H.;Sawhney,K.N.;Robertson,D.W.;Leander,J.D.
  9. J. Med. Chem. v.36 Synthesis and Anticonvulsant Activities of α-Heterocyclic α-Acetamido-N-benzylacetamide Derivatives Kohn,H.;Sawhney,K.N.;Bardel,P.;Robertson,D.W.;Leander,J.D.
  10. J. Pharm. Sci. v.73 Synthesis and Anticonvulsant Evaluation of N-Aminosuccinimides Kornet,M.J.
  11. J. Med. Chem. v.34 GABA uptake Inhibitors: Construction of a General Pharmacophore Model and Successful Prediction of a New Representative N'Goke,V.;Schlewer,G.;Linget,J.M.;Chambon,J.P.;Wermuth,C.G.
  12. Organic Functional Group Preparation v.III Sandler,S.R.;Karo,W.
  13. J. Med. Chem. v.37 Structure Activity Study of 5-Substituted 1-Carbobenzoxy-2-iminohydantoins as Potential Anticonvulsant Agents Sun,Z.Y.;Kwon,C.H.;Wurpel,N.D.
  14. Quantification and Evaluation of Anticonvulsants in Antiepileptic Drugs. (3rd ed.) General Principles, Experimental Section Swinyard,E.A.;Woodhead,J.H.;White,H.S.;Frankline,M.R.;Levy,R.(et al.)(ed.)
  15. Seizure disorder-A Pharmcological Approach to Treatment Wilder,B.J.
  16. J. Med. Chem. v.15 Para-substituted N-Acetyl-L(S)-and-D(R)-α-amino-N-phenylsuccinimides and -glutarimides. Substituent effects on Stereoselective Anticonvulsant Activity Witak,D.T.;Seth,S.K.;Baizman,E.R.;Wiebel,S.L.;Wolf,H.H.