New Selective and Potent 5-HT1B/1D Antagonists:  Chemistry and Pharmacological Evaluation of N-Piperazinylphenyl Biphenylcarboxamides and Biphenylsulfonamides

• Published in: Journal of medicinal chemistry 2000-02, Vol.43 (3), p.517-525
• Main Authors: Liao, Yi, Böttcher, Henning, Harting, Jürgen, Greiner, Hartmut, van Amsterdam, Christoph, Cremers, Thomas, Sundell, Staffan, März, Joachim, Rautenberg, Wilfried, Wikström, Håkan
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Serotoninergic system
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990397l

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, 10, 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.