Functionalized Amino Acids as Antiepileptic Agents

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Functionalized Amino AcidsasAntiepileptic Agents

• Leah M. Dees

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What is an Antiepileptic Agent?

• A drug that, when administered over a prolonged
  period, will decrease the incidence or severity
  of seizures occurring in epileptic patients.
• Current antiepileptic agents are ineffective in
  more than one-third of epileptic patients.

Macdonald, Robert L. Meldrum, Brian S.. In
Antiepileptic Drugs, 4th ed. Levy, R.H.,
Mattson, R.H., Meldrum, B.S., Eds. Raven Press
New York, 1995 pp 61-73.
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Current Antiepileptic Agents
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A Comparison

• Many current antiepileptic agents are very
  similar to one of the following structural basis

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General Structure
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A Comparison
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R1 Substituent
R2CH3, R3CH2Ph
R1CH3
R1(CH3)3C
R1(CH3)2CH
R1CH3CONHCH2
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R2 Substituent
R1CH3, R3CH2Ph
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R2 Substituent
R1CH3, R3CH2Ph
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R3 Substituents
R1CH3, R2CH3
CH2Ph
CH(Ph)2
CH2Ph-m-F
CH3
CH2Ph-m-OCH3
CH2CONHCH2Ph
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New Antiepileptic Agents

• Activity increased when a acetyl moiety was added
  to the amino terminus.

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New Antiepileptic Agents

• Activity was found to increase when an ether
  substituent was placed one atom from the C(2)
  site.

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New Antiepileptic Agents

• Activity increased when N-benzylamide was added
  to the carboxyl terminus (R3 CH2Ph).

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New Antiepileptic Agents
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Synthesis of New Antiepileptic Agents
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Stereochemistry
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Synthesis of the (S) Isomer
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Synthesis of the (R) Isomer
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New Antiepileptic Agents

• Activity decreased when the tetrahedral C(2) atom
  was replaced with a trivalent N.
• Note the loss stereochemistry.

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Mechanism of ActionFive Different FAA Affinity
Labels
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(R)-1
(R,S)-2
Phenobarbital
(S)-1
Phenytoin
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(R)-1
(R,S)-2
Phenobarbital
(S)-1
Phenytoin
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(R)-1
(R,S)-2
Phenobarbital
(S)-1
Phenytoin
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(R)-1
(R,S)-2
Phenobarbital
(S)-1
Phenytoin
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What this indicates

• (R)-4 and (R)-5 exhibit significant antiepileptic
  activity.
• Radioligands were not displaced, indicating that
  receptor binding does not take place.
• The activity of the (R) enantiomer is 10 to 22
  times more potent that the (S) enantiomer.
• Therefore, it seems that the FAA mechanism is
  related to the stereoselective binding to the
  receptor or the enzyme.
• The mechanism remains unknown.

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Problems with the Research

• The majority of the published articles measured
  seizure spread electronically (MES induced
  seizures).
• Other drugs that act for instance by altering
  metabolic or endocrine functions will not be
  detected.

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Conclusion

• Features increasing antiepileptic activity are
• COCH3 at the N-terminus
• NHCH2Ph at the C-terminus
• CH2OCH3 (or CH2OCH2CH3) at the C(2) site.
• (R) enantiomer
• Thus, the following show potential for future
  agents

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Conclusion

• The mechanism of action remains unknown.
• Receptor binding does NOT occur in common
  antiepileptic receptors.
• Stereoselective binding DOES occur.

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References

• 1. Andurkar, Shirdhar V. Beguin, Cecile
  Stables, James P. Kohn, Harold. Synthesis and
  Structural Studies of Aza Analogues of
  Functionalized Amino Acids New Anticonvulsant
  Agents. J. Med. Chem. 2001, 44, 1475-1478.
• 2. Choi, Daeock Stables, James P. Kohn, Harold.
  Synthesis and Anticonvulsant Activities of
  N-benzyl-2-acetamidopropionamide Derivatives. J.
  Med. Chem. 1996, 39, 1907-1916.
• Conley, Judith D. Kohn, Harold Fuctionalized
  DL-Amino Acid Derivatives. Potent New Agents for
  the Treatment of Epilepsy. J. Med. Chem. 1987,
  30, 567-574.
• Kohn, Harold Sawhney, Kailash N. LeGall,
  Philippe Conley, Judity D. Robertson, David W.
  Leander, J. David. Preparation and Anticonvulsant
  Activity of a Series of Functionalized ?-Aromatic
  and ?-Heteroaromatic Amino Acids. J.Med. Chem.
  1990, 33, 919-926.
• Kohn, Harold Sawhney, Kailash, Sawhney N.
  LeGall, Philippe Robertson, David W. Leander,
  J. David. Preparation and Anticonvulsant Activity
  of a Series of Functionalized ?-Heteroaromatic-Sub
  stituted Amino Acids. J.Med. Chem. 1991, 34,
  2444-2452.

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More References

• LeTiran, Arnaud Stables, James P. Kohn, Harold.
  Design and Evaluation of Affinity Labels of
  Functionalized Amino Acid Anticonvulsants. J.
  Med. Chem. 2002, 45, 4762-4773.
• Macdonald, Robert L. Meldrum, Brian S.. In
  Antiepileptic Drugs, 4th ed. Levy, R.H.,
  Mattson, R.H., Meldrum, B.S., Eds. Raven Press
  New York, 1995 pp 61-73.
• Shen, Min LeTiran, Arnaud Xiao, Yunde
  Golbraikh, Alexander Kohn, Harold Tropsha,
  Alexander. Quantitative Structure-Activity
  Relationship Analysis of Functionalized Amino
  Acid Anticonvulsant Agents Using k Nearest
  Neighbor and Simulated Annealing PLS Methods. J.
  Med. Chem.2002, 45, 2811-2823.