2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxamides with Selective Affinity for the 5-HT₄Receptor:  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).

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

“…Amidine 35 was prepared by reducing benzonitrile 19 and coupling with 2-(4-methylpiperazin-1-yl)ethanamine. [27] Scheme 1. 4 , THF, 0 8C!50 8C, 14-18 h, 2) 2-(4-methylpiperazin-1-yl)acetic acid, [26] …”

“…The residue was dissolved in CH 2 Cl 2 (4 mL), and together with Et 3 N (240 mL, 1.7 mmol) was added to a solution of 2-(4-methylpiperazin-1-yl)acetic acid [26] (81 mg, 0.51 mmol), EDC·HCl (160 mg, 750 mmol), and HO-Su (75 mg, 0.65 mmol) in CH 2 Cl 2 (4 mL), which had been stirred at 25 8C for 70 min prior. Stirring at 25 8C was continued for 16 h, the mixture was diluted with CH 2 Cl 2 (50 mL), washed with saturated aqueous NaHCO 3 (50 mL) and saturated aqueous NaCl (50 mL), dried (MgSO 4 N-[2-[(7-Methoxy-2-acridinyl)amino]-6-(phenylsulfanyl)benzyl]-2-(4-methyl-1-piperazinyl)ethanimidamide (35): 2-(4-Methylpiperazin-1-yl)ethanamine [27] (32 mg, 0.22 mmol) and AlMe 3 (2 m in toluene, 0.17 mL, 0.34 mmol) were added to nitrile 19 (50 mg, 0.11 mmol) in toluene (2 mL), and the mixture was stirred for 3 days at 100 8C. H 2 O (10 mL) was added, and the mixture was diluted with saturated aqueous Na 2 CO 3 (30 mL), extracted with EtOAc (3 40 mL), dried (MgSO 4 ), filtered, and concentrated.…”

Novel Water-Soluble Sedative-Hypnotic Agents: Isoindolin-1-one Derivatives

“…The 1-alkylpiperazines 35 were synthesized based on the literature 9) as shown in Chart 3. Specifically, ethyl 1-piperazinecarboxylate 38 and an appropriate alkyl halide were heated in the presence of potassium carbonate to afford ethyl esters 39, which were then heated with 47% hydrogen bromide to afford hydrobromides 40, which were then treated with sodium hydroxide to afford the 1-alkylpiperazines 35.…”

5-HT4 Receptor Antagonists: Structure-Affinity Relationships and Ligand- Receptor Interactions

“…Among them, the most interesting antagonist is DAU 6285 [121][122][123] (Figure 8), which underwent preclinical investigation as an antiarrhythmic agent [124,125] and in GI disorders [126]. However, no recent development has been reported for On the other hand, analogs with a substituent on the nitrogen atom less voluminous than a butyl group are devoid of affinity at the 5-HT 4 R. These results confirm that both the presence of a voluminous substituent in the basic [127] have described a series of benzimidazolones 3 as 5-HT 4 R ligands (Figure 8) with selectivity over 5-HT 3 and D 2 receptors. In these amides, 5-HT 4 R functional activity is modulated by the substituent at position 3 of the aromatic ring (R) and the substituent on the piperazine ring (R'), and this trend seems to support the hypothesis of two different binding sites for 5-HT 4 R agonists and antagonists, suggested by Langlois et al [101].…”