title: (E)-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid derivatives. A novel class of glycine site antagonists.
abstract: 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.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Balsamini
authors.forename: A
authors.initials: A
authors.lastname: Bedini
authors.forename: G
authors.initials: G
authors.lastname: Diamantini
authors.forename: G
authors.initials: G
authors.lastname: Spadoni
authors.forename: A
authors.initials: A
authors.lastname: Tontini
authors.forename: G
authors.initials: G
authors.lastname: Tarzia
authors.forename: R
authors.initials: R
authors.lastname: Di Fabio
authors.forename: A
authors.initials: A
authors.lastname: Feriani
authors.forename: A
authors.initials: A
authors.lastname: Reggiani
authors.forename: G
authors.initials: G
authors.lastname: Tedesco
authors.forename: R
authors.initials: R
authors.lastname: Valigi
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018684:Glycine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D016202:N-Methylaspartate / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; C111349:4,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid; D000178:Acrylamides; D000927:Anticonvulsants; D018684:Glycine Agents; D007211:Indoles; D011758:Pyrroles; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate