Synthesis and pharmacological evaluation of a series of new 1,4-disubstituted 3-methyl-piperidine analgesics
| Autor: | Denny Wright, Nhora Lucia Lalinde, John Moliterni, Theodore C. Spaulding, Spencer H Kenneth, Frieda G. Rudo, Michael H. Ossipov |
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| Rok vydání: | 1990 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 33:2876-2882 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00172a032 |
| Popis: | The synthesis and intravenous analgesic activity of a series of 3-methyl-4-(N-phenyl amido)piperidines, entries 34-79, is described. The methoxyacetamide pharmacophore produced a series of compounds with optimal analgesic potency and short duration of action. cis-42 was 13,036 times more potent than morphine and 29 times more potent than fentanyl; however, the corresponding diastereomer 43 was only 2778 and 6 times more potent, respectively. Compounds 40, 43, 47, and 57 are extremely short acting; all had durations of action of about 2 min, which was about 1/5 of that of fentanyl in the mouse hot-plate test at a dose equivalent to 2 times the ED50 analgesic dose. Among the many compounds that displayed exceptional analgesic activity, duration of action was one of the main factors for choosing a candidate for further pharmacological investigation. At present, cis-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-3-meth yl-4- [N-in equilibrium 2-fluorophenyl)methoxyacetamido]piperidine hydrochloride (40) (Anaquest, A-3331.HCl, Brifentanil) is in clinical evaluation. Opiate analgesics that possess short duration of action are excellent candidates for short surgical procedures in an outpatient setting where a rapid recovery is required. |
| Databáze: | OpenAIRE |
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