3-(2-(N-PHENYLCARBAMOYL)VINYL)PYRROLE-2-CARBOXYLIC ACID-DERIVATIVES -A NOVEL CLASS OF GLYCINE SITE ANTAGONISTS

The synthesis and preliminary biological evaluation of novel 3-(2-(N-p henylcarbamoyl)vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, a lkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for their in v itro affinity at the strychnine-insensitive glycine-binding site of th e N-methyl-D-aspartate (NMDA) receptor complex. In the [H-3]glycine bi nding assay ,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2 -carbox ylic acid 6w (pK(i) = 7.95 +/- 0.01) and the 4-bromo-5-methyl 6j (pK(i ) = 7.24 +/- 0.01) and 4,5-dimethyl 6g (pK(i) = 6.70 +/- 0.03) analogu es were the most active compounds of the series. Qualitative structure -activity analysis points to a negative correlation between bulk of th e C-4 and C-5 substituents and affinity which is enhanced by halo-subs tituents. QSAR analysis by the Hansch descriptors F, R, pi, and MR, on a subset of compounds with pK(i) greater than or equal to 4, indicate s that electron-withdrawing groups at C-4 and C-5 enhance the affinity . Bulk and lipophilicity are also relevant for the substituents at the se positions. 6g was found to be a full antagonist (a = 0; enhancement of the [H-3]TCP binding). The in vivo potency of 6g, 6j, and 6w was e valuated by the inhibition of NMDA-induced convulsions in mice by both the iv and po routes; 6w was the most active compound (ED50 = 3 X 10( -3) (0.8-10) g/kg, iv and 30 x 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 .