title: 4-Aminoethylpiperazinyl aryl ketones with 5-HT₁A/5-HT₇ selectivity.
abstract: The well-known 5-HT(1A)/5-HT(7) 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-HT(7)R and 5-HT(1A)R revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT(7)R but parallel in 5-HT(1A)R, and this observation is well matched with the previous report which claimed that 5-HT(7)R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT(1A)R selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT(7)R and 5-HT(1A)R seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, South Korea.
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Hyo Seon
authors.initials: HS
authors.lastname: Lee
authors.forename: Sora
authors.initials: S
authors.lastname: Kim
authors.forename: Suh Young
authors.initials: SY
authors.lastname: Cho
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007659:Ketones; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A