Kim, Mi Kyoung Lee, Hyo Seon Kim, Sora Cho, Suh Young Roth, Bryan L. Chong, Youhoon Choo, Hyunah 2024-01-20T15:33:18Z 2024-01-20T15:33:18Z 2021-09-04 2012-01-15 0968-0896 https://pubs.kist.re.kr/handle/201004/129640 The well-known 5-HT1A/5-HT7 selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4-aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT7R and 5-HT1AR revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT7R but parallel in 5-HT1AR, and this observation is well matched with the previous report which claimed that 5-HT7R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT1AR selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT7R and 5-HT1AR seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds. (C) 2011 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD SITE-DIRECTED MUTAGENESIS RECEPTOR 5-HT7 ANTAGONIST DEPRESSION 4-Aminoethylpiperazinyl aryl ketones with 5-HT1A/5-HT7 selectivity Article 10.1016/j.bmc.2011.11.005 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.20, no.2, pp.1139 - 1148 BIOORGANIC & MEDICINAL CHEMISTRY 20 2 1139 1148 scie scopus 000299496100064 2-s2.0-84855788946 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article SITE-DIRECTED MUTAGENESIS RECEPTOR 5-HT7 ANTAGONIST DEPRESSION Serotonergic receptor 5-HT1AR 5-HT7R Selectivity 4-Aminoethylpiperazinyl aryl ketones