| Abstract
| - 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 selective5-HT1B/1D antagonists were synthesized and evaluated pharmacologically. Their receptor bindingprofiles were comparable to that of 1. The 1,3,4-oxadiazole isomer 2 and the 4‘-aminocarbonyland 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, 10, 11b (O-demethylated derivative of 2), 13a (O-methylsulfonyl analogue of 2), and 16 (which differsfrom 2 with a sulfonamide linker) showed more pronounced effects in the K+-induced 5-HTrelease in the cortex of guinea pig than did 1 and 3 (SB224289). Compounds 2, 9, and 10 wereequally potent as 1 in rabbit saphenous vein model (pA2> 9). A biochemical study of 2 with invivo microdialysis in the rat brain showed that it is capable of augmenting citalopram (aselective 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 andlog D values of these compounds were calculated. This study contributes to the SAR study ofN-piperazinylphenyl biphenylcarboxamides as selective and potent 5-HT1B/1D antagonists.
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