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Leopoldo M, Lacivita E, Contino M, Colabufo NA, Berardi F, Perrone R: Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2. J Med Chem. 2007 Aug 23;50(17):4214-21. Epub 2007 Jul 25.
Here we report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides 16-29 that were designed to elucidate both structure-affinity and -activity relationships for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compounds were determined. A series of substituents covering a wide range of electronic, steric, and polar properties was evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CH (CH3) 2, N (CH3) 2, CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl) phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-pipera zinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamid e (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazi nehexanamide (22) were identified as potent 5-HT7 receptor agonists (Ki = 0.13-1.1 nM, EC50 = 0.90-1.77 microM), showing selectivity over 5-HT1A, 5-HT2A, and D2 receptors. |
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