Receptor-Based Pharmacophores for Serotonin 5-HT₇R AntagonistsImplications to Selectivity

Abstract

A set of 31 diversified 5-HT7 receptor antagonists was automatically docked to a conformational ensemble of rhodopsin-based 5-HT7R models (flexible docking). It was found that ergolines, aporphines, and tricyclic psychotropic agents were always docked in a pocket formed by TMHs 4-6, and besides the main ionic bond with Asp3.32, they had specific interactions with Phe6.52, Phe6.51, Trp6.48, and Ser5.42. The arylpiperidine, arylpiperazine, or beta-carboline fragment of the complex ligands occupied the same pocket, whereas the terminal amide/imide part of those compounds reached the second cavity formed by TMHs 7-3 and interacted with Phe3.28, Arg7.36, and Tyr7.43. A similar orientation of selective antagonists of the group of arylsulfonamidoalkylamines was observed, that is, the sulfonamide part was located in the second pocket. Coherent docking results allowed the generation of two receptor-based pharmacophores: first containing features necessary for high 5-HT7R affinity and the other defining selectivity for this receptor subtype. The latter model indicated the importance of specific interactions with the residues of the TMHs 7-3 pocket (especially nonconserved Arg7.36) for selectivity over other monoamine GPCRs.

Synthesis, 5-Hydroxytryptamine_1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

“…29) A second interaction between the indole moiety and Phe 6.52 was also observed. These docking poses are highly consistent with the binding mode of longchain arylpiperazines proposed by Kołaczkowski et al and Nowack et al 30,31) Additionally, the indole moiety was oriented towards helices I, II and VII, in a favorable position to establish a π-π interaction with the aromatic ring of Tyr 2.54 at the end of helix II.…”

Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders

“…It should be noted that the binding mode for 182 (SB-269970) suggested by Kołaczkowski et al (2006) differed from that proposed by Vermeulen et al (2004). Apart from the electrostatic interaction between the protonated nitrogen atom with Asp 3.32 , Vermeulen and coworkers suggested: C-H˙˙π interactions between Ph 7.38 and the piperidine ring; interaction between the sulfonamide oxygen and the hydroxyl group of Thr 6.45 ; interaction between the phenolic-OH and Thr 6.45 .…”

“…The first receptor-based pharmacophore for the 5-HT 7 receptor was constructed by Kołaczkowski et al (2006), which evaluated, through docking studies, the mode of interaction of selective and nonselective antagonists with the receptor binding site. It was hypothesized that selective and nonselective antagonists might have different binding modes with the receptor.…”

Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

“…2). 23 Subsequently, setting the propionyl as linker chain, we introduced different substituents at the HYD/Ar 2 domain. When the Ar 2 was a benzyl group, at the HYD/Ar 1 domain we introduced different substituted piperazines such as: 4-, 3-, and 2-ClC 6 H 4 , 4-and 2-MeOC 6 H 4 , 2-pyridyl, and 2-pyrimidyl (compounds 13-29).…”