180207-83-4Relevant articles and documents
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
Tapia, Inés,Alonso-Cires, Luisa,López-Tudanca, Pedro Luis,Mosquera, Ramón,Labeaga, Luis,Innerárity, Ana,Orjales, Aurelio
, p. 2870 - 2880 (2007/10/03)
A series of 2,3-dihydro-2-oxo-1H-benzimidazole-l-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 (K(i) = 6.7-75.4 nM) for the 5-HT4 receptor with selectivity over 5-HT3 and D2 receptors and moderate antagonist activity (pK(b) = 6.19- 7.73). Compounds with an isopropyl substituent in the 3-benzimidazole position exhibited moderate and selective 5-HT4 affinity (K(i) ≥ 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, pK(b) = 7.94). N-Butyl quaternization of 5a led to an improvement in affinity for the 5-HT4 receptor and maintained the high partial agonist activity (5r, K(i) = 66.3 nM, i.a. = 0.93).
