title: 2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxamides with selective affinity for the 5-HT(4) receptor: synthesis and structure-affinity and structure-activity relationships of a new series of partial agonist and antagonist derivatives.
abstract: A series of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide derivatives bearing a piperazine moiety was synthesized. Their in vitro 5-HT(4), 5-HT(3), and D(2) receptors affinities were evaluated by radioligand binding assay. For selected compounds functional studies at the 5-HT(4) 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-HT(4) receptor with selectivity over 5-HT(3) and D(2) 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-HT(4) 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-HT(4) 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-HT(4) 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-HT(4) 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-HT(4) receptor and mantained the high partial agonist activity (5r, K(i) = 66.3 nM, i.a. = 0.93).
authors.affiliation: Departamento de Investigación, FAES, S.A., Máximo Aguirre 14, 48940 Leioa, Vizcaya, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Tapia
authors.forename: L
authors.initials: L
authors.lastname: Alonso-Cires
authors.forename: P L
authors.initials: PL
authors.lastname: López-Tudanca
authors.forename: R
authors.initials: R
authors.lastname: Mosquera
authors.forename: L
authors.initials: L
authors.lastname: Labeaga
authors.forename: A
authors.initials: A
authors.lastname: Innerárity
authors.forename: A
authors.initials: A
authors.lastname: Orjales
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D018728:Entorhinal Cortex / Q000378:metabolism; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001562:Benzimidazoles; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4