New selective and potent 5-HT 1B/1D antagonists: Chemistry and pharmacological evaluation of N-piperazinylphenyl biphenylcarboxamides and biphenylsulfonamides
| Autor: | Liao, Y, Bottcher, H, Harting, J, Greiner, H, van Amsterdam, C, Cremers, T, Sundell, S, Marz, J, Rautenberg, W, Wikstrom, H |
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| Přispěvatelé: | Faculty of Science and Engineering, Synthesis and Analysis, Groningen Research Institute of Pharmacy, Medicinal Chemistry and Bioanalysis (MCB) |
| Jazyk: | Dutch; Flemish |
| Rok vydání: | 2000 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry, 3, 517-525. AMER CHEMICAL SOC Journal of Medicinal Chemistry, 43(3), 517-525. AMER CHEMICAL SOC |
| ISSN: | 0022-2623 |
| Popis: | A series of new analogues of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (1; GR127935) as potent and selective 5-HT1B/1D antagonists were synthesized and evaluated pharmacologically. Their receptor binding profiles were comparable to that of 1. The 1,3,4-oxadiazole isomer 2 and the 4'-aminocarbonyl and 4'-amidinyl analogues (9 and 10) of 1 had higher affinities at the rat 5-HT1B receptor (IC50 = 0.93, 1.3, and 0.5 nM, respectively) and calf 5-HT1D receptor (IC50 = 37, 10, and 3 nM, respectively) than did 1 (1.6 and 52 nM for rat 5-HT1B and calf 5-HT1D receptors, respectively). In the functional in vitro testing of 5-HT1B/1D antagonistic properties, 2, 9, 18, 11b (O-demethylated derivative of 2), 13a (O-methylsulfonyl analogue of 2), and 16 (which differs from 2 with a sulfonamide linker) showed more pronounced effects in the K+-induced 5-HT release in the cortex of guinea pig than did 1 and 3 (SB224289). Compounds 2, 9, and 10 were equally potent as 1 in rabbit saphenous vein model (pA(2) > 9). A biochemical study of 2 with in vivo microdialysis in the rat brain showed that it is capable of augmenting citalopram (a selective serotonin reuptake inhibitor, SSRI) induced 5-HT release in rat ventral hippocampus, while preventing the decrease in acetylcholine release elicited by citalopram administration. The molecular structure of 2 was determined by single-crystal X-ray analysis. The log P and log D values of these compounds were calculated. This study contributes to the SAR study of N-piperazinylphenyl biphenylcarboxamides as selective and potent 5-HT1B/1D antagonists. |
| Databáze: | OpenAIRE |
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