Background: Epilepsy is a disease of the central nervous system that affects approximately
50 million individuals worldwide. Although several new drugs have been marketed in the last 25 years,
almost one-third of patients are not protected. In many cases, currently available drugs produce undesirable
side effects. As a result, a need exists for novel anticonvulsants with unique mechanisms of action
and minimal side effects.
Methods: A mixed anhydride coupling procedure and standard deprotection procedures were utilized to
prepare 36 α-amino acid amides. All final products were evaluated in mice and rats utilizing a standard
battery of anticonvulsant tests.
Results: α-Amino acids containing a 2,6-dimethylanilide group exhibited anticonvulsant activity in the
maximal electroshock seizure test and 6 Hz test in mice and rats. A small, branched-chain on the α-
carbon generally maintained or enhanced anticonvulsant activity in the maximal electroshock seizure
test. The (R)-α-amino acid amides were typically more potent and slightly more neurotoxic than the
corresponding (S)-enantiomers. The valine dimethylanilide (R)-42 was highly active in the MES test in
mice (ED50 = 3.6mg/kg) and rats (ED50 = 3.8 mg/kg). (R)-42 also demonstrated excellent anticonvulsant
activity in the 6 Hz, picrotoxin, and corneal kindled mouse tests. Furthermore, (R)-42 did not lower
seizure threshold when evaluated in the intravenous metrazol seizure test.
Conclusion: α-Amino acid 2,6-dimethylanilides exhibited potent activity in a variety of anticonvulsant
tests in mice and rats. The valine derivative (R)-42 represents a promising compound for potential use in
complex partial seizures.