Carolina Campos-Rodríguez
◽
José G. Trujillo-Ferrara
◽
Ameyali Alvarez-Guerra
◽
Irán M. Cumbres Vargas
◽
Roberto I. Cuevas-Hernández
◽
...
Background:
Thalidomide, the first synthesized phthalimide, has demonstrated sedative-
hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides
have an interesting chemical structure that confers important biological properties.
Objective:
Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral
phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic
and anticonvulsant effects were tested.
Method:
Homology modeling and molecular docking were employed to predict recognition of the
analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the
open field test and elevated plus maze (EPM). The compounds were tested in mouse models of
acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP;
10 mg/kg).
Results:
The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased
locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased
locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg,
and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ
model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP
and R-TASP (316 mg/kg) lowered the convulsive and death rate.
Conclusion:
The chiral compounds exhibited a non-competitive NMDAR antagonist profile and
the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity
for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to
be supported by the in silico studies, which evidenced a high affinity of phthalimides for the
hNMDAR and mGluR type 1.
