+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Identification of the binding sites and selectivity of sarpogrelate, a novel 5-HT2 antagonist, to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling

Identification of the binding sites and selectivity of sarpogrelate, a novel 5-HT2 antagonist, to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling

Life Sciences 73(2): 193-207

The aim of the present study was to investigate the binding sites interactions and the selectivity of sarpogrelate to human 5-HT(2) receptor family (5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes) using molecular modeling. Rhodopsin (RH) crystal structures were used as template to build structural models of the human serotonin-2A and -2C receptors (5-HT(2A)R, 5-HT(2C)R), whereas for 5-HT(2B)R, we used our previously published three-dimensional (3D) models based on bacteriorhodopsin (BR). Sarpogrelate, a novel 5-HT(2)R antagonist, was docked to the receptors. Molecular dynamics (MD) simulations produced the strongest interaction for 5-HT(2A)R/sarpogrelate complex. Upon binding, sarpogrelate constraints aromatic residues network (Trp(3.28), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2A)R; Phe(3.35), Phe(6.51), Trp(7.40) in 5-HT(2B)R; Trp(3.28), Phe(3.35), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2C)R) in a stacked configuration, preventing activation of the receptor. The models suggest that the structural origin of the selectivity of sarpogrelate to 5-HT(2A)R vs both 5-HT(2B)R and 5-HT(2C)R comes from the following results: (1) The tight interaction between the antagonist and the transmembrane domain (TMD) 3. Asp(3.32) neutralizes the cationic head and interacts simultaneously with carboxylic group hydrogen of the antagonist molecule. (2) Due to steric hindrance, Ser(5.46) (vs Ala(5.46) in 5HT(2B) and 5HT(2C)) prevents sarpogrelate to enter deeply inside the hydrophobic core of the helix bundle and to interact with Pro(5.50). (3) The side chain of Ile(4.56) (vs Ile(4.56) in 5HT(2B)R and Val(4.56) in 5HT(2C)R) constraints sarpogrelate to adjust its position by translating toward the strongly attractive Asp(3.32). These results are in good agreement with binding affinities (pKi) of sarpogrelate for 5-HT(2) receptor family expressed in transfected cell.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 010788737

Download citation: RISBibTeXText

PMID: 12738034

DOI: 10.1016/s0024-3205(03)00227-3

Related references

5-HT2c receptor antagonists, but not a 5-HT2A or 5-HT2B receptor antagonist, attenuate haloperidol-induced catalepsy in rat. British Journal of Pharmacology 125(PROC Suppl. ): 65P, 1998

(1R, 3S)-(-)-trans-PAT: a novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity. European Journal of Pharmacology 615(1-3): 1-9, 2009

Inverse agonist activity of sarpogrelate, a selective 5-HT2A-receptor antagonist, at the constitutively active human 5-HT2A receptor. Journal of Pharmacological Sciences 102(2): 189-195, 2006

Multiparameter optimization in CNS drug discovery: design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT₂C) receptor agonists with exquisite functional selectivity over 5-HT₂A and 5-HT₂B receptors. Journal of Medicinal Chemistry 57(12): 5258-5269, 2014

Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors. Naunyn-Schmiedeberg's Archives of Pharmacology 359(1): 1-6, 1999

Binding of N-2-substituted pyrido(4,3-b)indole analogs of spiperone at human 5-HT2A, 5-HT2B, and 5-HT2C serotonin receptors. Medicinal Chemistry Research 6(3): 197-210, 1996

5-Methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole: a novel 5-HT2C/5-HT2B receptor antagonist with improved affinity, selectivity, and oral activity. Journal of Medicinal Chemistry 38(14): 2524-2530, 1995

Rapid desensitisation of human 5-HT2B receptors measured by fluorimetry Comparison with human 5-HT2A and 5-HT2C VSV and INI receptor isoforms. British Journal of Pharmacology 128(PROC Suppl. ): 287P, 1999

Molecular and pharmacological characterization of serotonin 5-HT2A and 5-HT2B receptor subtypes in dog. European Journal of Pharmacology 513(3): 181-192, 2005

Mechanism of inverse agonist action of sarpogrelate at the constitutively active mutant of human 5-HT2A receptor revealed by molecular modeling. Biological and Pharmaceutical Bulletin 35(9): 1553-1559, 2013

Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B. Acs Chemical Biology 11(5): 1372-1382, 2017

Identification of binding sites of prazosin, tamsulosin and KMD-3213 with a1-adrenergic receptor subtypes by molecular modeling. Life Sciences 71(21): 31-41, 2002

Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding. Molecular Biosystems 5(12): 1877-1888, 2010

Identification of binding sites of prazosin, tamsulosin and KMD-3213 with alpha(1)-adrenergic receptor subtypes by molecular modeling. Life Sciences 71(21): 2531-2541, 2002

Functionally rightward-shifted serotonin 5-HT2C receptor agonists are inactive at 5-HT2A and 5-HT2B receptors. Society for Neuroscience Abstracts 27(1): 693, 2001