jm981098j_si_001.pdf (666.22 kB)

2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxamides with Selective Affinity for the 5-HT4 Receptor:  Synthesis and Structure−Affinity and Structure−Activity Relationships of a New Series of Partial Agonist and Antagonist Derivatives

Download (666.22 kB)
journal contribution
posted on 02.07.1999, 00:00 by Inés Tapia, Luisa Alonso-Cires, Pedro Luis López-Tudanca, Ramón Mosquera, Luis Labeaga, Ana Innerárity, Aurelio Orjales
A series of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide derivatives bearing a piperazine moiety was synthesized. Their in vitro 5-HT4, 5-HT3, and D2 receptors affinities were evaluated by radioligand binding assay. For selected compounds functional studies at the 5-HT4 receptor were made by using precontracted (by carbachol) preparations of rat esophageal tunica muscularis mucosae (TMM). The influence of the 3-substituent of the benzimidazole ring, the 4-substituent of the piperazine moiety, and the alkylene spacer was studied. Compounds with an ethyl or a cyclopropyl substituent in the 3-position of the benzimidazole ring showed moderate to high affinity (Ki = 6.7−75.4 nM) for the 5-HT4 receptor with selectivity over 5-HT3 and D2 receptors and moderate antagonist activity (pKb = 6.19−7.73). Compounds with an isopropyl substituent in the 3-benzimidazole position exhibited moderate and selective 5-HT4 affinity (Ki ≥ 38.9 nM) and a partial agonist activity (5a, i.a. = 0.94) higher than that of the reference compound BIMU 8 (i.a. = 0.70). This reversal of the pharmacological activity due only to a small structural difference might confirm the existence of two binding sites on the 5-HT4 receptor. In the alkylene spacer, a two-methylene chain is favorable to optimize the affinity and the antagonist or the partial agonist activity. In the ethyl and cyclopropyl series, 5-HT4 antagonist activity seems to be unrelated to the size of the 4-substituent of the piperazine moiety, whereas a methyl group is optimal for high partial agonist activity in the isopropyl series; however, the presence of a butyl substituent is a favorable pattern for 5-HT4 antagonism and even causes a reversal of the pharmacological profile in the isopropyl series (5h, pKb = 7.94). N-Butyl quaternization of 5a led to an improvement in affinity for the 5-HT4 receptor and mantained the high partial agonist activity (5r, Ki = 66.3 nM, i.a. = 0.93).