Balsamini C, Bedini A, Diamantini G, Spadoni G, Tontini A, Tarzia G, Di Fabio R, Feriani A, Reggiani A, Tedesco G, Valigi R
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino, Italy.
J Med Chem. 1998 Mar 12;41(6):808-20. doi: 10.1021/jm970416w.
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, pi, and MR, on a subset of compounds with pKi > or = 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 (alpha = 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 i.v. and po routes; 6w was the most active compound (ED50 = 3 x 10(-3) (0.8-10) g/kg, i.v. and 30 x 10(-3) (4.5-61) g/kg, p.o.). The results of this study indicate that the 3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine antagonists.
报道了在吡咯环的4-位和5-位带有烷基、酰基、烷氧基、苯基和卤代取代基的新型（E）-3-（2-（N-苯基氨基甲酰基）乙烯基）吡咯-2-羧酸的合成及初步生物学评价。研究了这些化合物对N-甲基-D-天冬氨酸（NMDA）受体复合物中士的宁不敏感甘氨酸结合位点的体外亲和力。在[³H]甘氨酸结合试验中，（E）-4,5-二溴-3-（2-（N-苯基氨基甲酰基）乙烯基）吡咯-2-羧酸6w（pKi = 7.95±0.01）以及4-溴-5-甲基类似物6j（pKi = 7.24±0.01）和4,5-二甲基类似物6g（pKi = 6.70±0.03）是该系列中活性最高的化合物。定性构效分析表明，C-4和C-5取代基的体积与亲和力呈负相关，卤代取代基可增强这种亲和力。通过Hansch描述符F、R、π和MR对pKi≥4的一部分化合物进行QSAR分析表明，C-4和C-5上的吸电子基团可增强亲和力。这些位置上取代基的体积和亲脂性也很重要。发现6g是一种完全拮抗剂（α = 0；增强[³H]TCP结合）。通过静脉注射和口服途径抑制小鼠体内NMDA诱导的惊厥，评估了6g、6j和6w的体内效力；6w是活性最高的化合物（静脉注射ED50 = 3×10⁻³（0.8 - 10）g/kg，口服30×10⁻³（4.5 - 61）g/kg）。本研究结果表明，3,4-二取代吡咯-2-羧酸酯是设计新型甘氨酸拮抗剂的新模板。
