Synthetic antidiarrheal agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides

Stokbroekx, Raymond A.; Vandenberk, J.; Heertum, Albert H. M. T. Van; Laar, G. M. L. W. Van; Aa, M. J. M. C. Van Der; Bever, Willem F. M. Van; Janßen, Paul

doi:10.1021/jm00265a009

Cited by 72 publications

(25 citation statements)

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“…The preparation of [ 11 C] 3 , required a convenient synthesis of the primary amide 1 , a compound which, as far as we are aware, has only been mentioned twice in the literature, but without synthesis details 20, 27. The synthesis of 1 was accomplished by a new route in two steps from commercially available materials.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Evaluation of [N-methyl-¹¹C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

et al. 2008

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Abstract[ 11 C]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-11 C]N-desmethyl-loperamide ([ 11 C] dLop; [ 11 C]3) precludes quantification. We considered that [ 11 C]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [ 11 C]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [ 11 C]iodomethane to give [ 11 C]3. After administration of [ 11 C]3 to wild type mice, brain radioactivity uptake was very low. In P-gp (mdr-1a (−/−)) knockout mice, brain uptake of radioactivity at 30 min increased about 3.5 fold by PET measures, and over seven-fold by ex vivo measures. In knockout mice, brain radioactivity was predominantly (90%) unchanged radiotracer. In monkey PET experiments, brain radioactivity uptake was also very low, but after P-gp blockade increased more than seven-fold. [ 11 C]3 is an effective new radiotracer for imaging brain P-gp function and, in favor of future successful quantification, appears free of extensive brain-penetrant radiometabolites.

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Section: Discussionmentioning

confidence: 99%

Synthesis and Evaluation of [N-methyl-¹¹C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

et al. 2008

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“…(8). The radiochemical purity was virtually 100% as determined by thin-layer chromatography (T.L.C.)…”

Section: [14 C] Loperamide Hydrochloridementioning

confidence: 99%

Disposition and metabolism of [14C]loperamide in rats

Miyazaki

Nambu

Matsunaga

et al. 1979

European Journal of Drug Metabolism and Pharmacokinetics

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Following oral administration of [14C]loperamide hydrochloride in 1 mg/kg to rats, plasma levels of radioactivity reached maximum at 4 hrs and decreased with a half-life of 4.1 hrs. Radioactivity in 96-hr feces accounted for 95% of the dose, with 30% associated with unchanged drug, while that in urine only 3.5%. Radioactivity in 48-hr bile accounted for 42% of the dose associated entirely with metabolites. 3% of the dose was found at the level of the enterohepatic cycles. These findings show that about 70% of the dose with absorbed by intestine, the target tissue of the drug, a portion (30%) of which was excreted back into intestinal cavity after demethylation, while the remaining 40% transferred to liver by which it was extracted mostly, metabolized extensively and excreted largely into bile, as supported by in vitro demethylating activity in gut segments but none in gut contents, and by in situ marked hepatic extraction of the drug. Main metabolic pathways involved are described.

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“…Loperamide is a synthetic piperidine derivative that is effective for the treatment of a variety of diarrhea syndromes, including acute, nonspecific (infectious) diarrhea, traveler's diarrhea, and chemotherapy-related and protease inhibitor associated diarrhea [1,2]. Loperamide is effective for the gut-directed symptoms of diarrhea in patients with painless diarrhea or diarrhea-predominant irritable bowel syndrome.…”

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confidence: 99%

Metabolomics approach to serum biomarker for loperamide-induced constipation in SD rats

et al. 2014

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Loperamide has long been known as an opioid-receptor agonist useful as a drug for treatment of diarrhea resulting from gastroenteritis or inflammatory bowel disease as well as to induce constipation. To determine and characterize putative biomarkers that can predict constipation induced by loperamide treatment, alteration of endogenous metabolites was measured in the serum of Sprague Dawley (SD) rats treated with loperamide for 3 days using 1H nuclear magnetic resonance (1H NMR) spectral data. The amounts and weights of stool and urine excretion were significantly lower in the loperamide-treated group than the No-treated group, while the thickness of the villus, crypt layer, and muscle layer was decreased in the transverse colon of the same group. The concentrations of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatinine (Cr) were also slightly changed in the loperamide-treated group, although most of the serum components were maintained at a constant level. Furthermore, pattern recognition of endogenous metabolites showed completely separate clustering of the serum analysis parameters between the No-treated group and loperamide-treated group. Among 35 endogenous metabolites, four amino acids (alanine, glutamate, glutamine and glycine) and six endogenous metabolites (acetate, glucose, glycerol, lactate, succinate and taurine) were dramatically decreased in loperamide-treated SD rats. These results provide the first data pertaining to metabolic changes in SD rats with loperamide-induced constipation. Additionally, these findings correlate the changes in 10 metabolites with constipation.

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Synthetic antidiarrheal agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides

Cited by 72 publications

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Synthesis and Evaluation of [N-methyl-¹¹C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

Synthesis and Evaluation of [N-methyl-¹¹C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

Disposition and metabolism of [14C]loperamide in rats

Metabolomics approach to serum biomarker for loperamide-induced constipation in SD rats

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Synthetic antidiarrheal agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides

Cited by 72 publications

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Synthesis and Evaluation of [N-methyl-11C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

Synthesis and Evaluation of [N-methyl-11C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

Disposition and metabolism of [14C]loperamide in rats

Metabolomics approach to serum biomarker for loperamide-induced constipation in SD rats

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Product

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Synthesis and Evaluation of [N-methyl-¹¹C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

Synthesis and Evaluation of [N-methyl-¹¹C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function