Balsamini, C., Bedini, A., Diamantini, G., Spadoni, G., Tontini, A., Tarzia, G., Fabio, R. Di, Feriani, A., Reggiani, A., Tedesco, G., and Valigi, R.
The synthesis and preliminary biological evaluation of novel (E)-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for their in vitro affinity at the strychnine-insensitive glycine-binding site of the N-methyl-d-aspartate (NMDA) receptor complex. In the [3H]glycine binding assay (E)-4,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid 6w (pKi = 7.95 ± 0.01) and the 4-bromo-5-methyl 6j (pKi = 7.24 ± 0.01) and 4,5-dimethyl 6g (pKi = 6.70 ± 0.03) analogues were the most active compounds of the series. Qualitative structure−activity analysis points to a negative correlation between bulk of the C-4 and C-5 substituents and affinity which is enhanced by halo-substituents. QSAR analysis by the Hansch descriptors F, R, π, and MR, on a subset of compounds with pKi ≥ 4, indicates that electron-withdrawing groups at C-4 and C-5 enhance the affinity. Bulk and lipophilicity are also relevant for the substituents at these positions. 6g was found to be a full antagonist (α = 0; enhancement of the [3H]TCP binding). The in vivo potency of 6g, 6j, and 6w was evaluated by the inhibition of NMDA-induced convulsions in mice by both the iv and po routes; 6w was the most active compound (ED50 = 3 × 10-3 (0.8−10) g/kg, iv and 30 × 10-3 (4.5−61) g/kg, po). The results of this study indicate that the 3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine antagonists.