Molecular determinants of ligand-directed signaling for the histamine H1 receptor

Booth, Raymond G.; Fang, Liangjuan; Wilczyński, Andrzej; Sivendren, S.; Sun, Zhi; Travers, Sean; Bruysters, Mwp; Sansuk, Kamonchanok; Leurs, Rob

doi:10.1007/s00011-007-0621-3

Cited by 9 publications

(8 citation statements)

References 8 publications

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“…Results are summarized in Table 1. Consistent with previous reports, 12,20,24 the parent analog, PAT, binds stereoselectively at 5-HT 2 receptor subtypes and at H 1 receptors, with about 3–15-fold higher affinity apparent for the (−)- over (+)-enantiomer, depending on receptor type. The (−)- trans enantiomers of the 4-(3′-[F, Cl, Br, CF 3 , NO 2 ]-phenyl) analogs ( 5a-5e ) also had higher affinity than the corresponding (+)-enantiomers at all three 5-HT 2 subtypes and at H 1 receptors.…”

Section: Pharmacological Characterizationsupporting

confidence: 91%

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

Sakhuja

Kondabolu

Córdova-Sintjago

et al. 2015

Bioorganic & Medicinal Chemistry

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Syntheses were undertaken of derivatives of (2S, 4R)-(−)-trans-4-phenyl-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (4-phenyl-2-dimethylaminotetralin, PAT), a stereospecific agonist at the serotonin 5-HT2C G protein-coupled receptor (GPCR), with inverse agonist activity at 5-HT2A and 5-HT2B GPCRs. Molecular changes were made at the PAT C(4)-position, while preserving N, N-dimethyl substitution at the 2-position as well as trans-stereochemistry, structural features previously shown to be optimal for 5-HT2 binding. Affinities of analogs were determined at recombinant human 5-HT2 GPCRs in comparison to the phylogenetically closely-related histamine H1 GPCR, and in silico ligand docking studies were conducted at receptor molecular models to help interpret pharmacological results and guide future ligand design. In most cases, C(4)-substituted PAT analogs exhibited the same stereoselectivity ([−]-trans > [+]-trans) as the parent PAT across 5-HT2 and H1 GPCRs, albeit, with variable receptor selectivity. 4-(4′-substituted)-PAT analogs, however, demonstrated reversed stereoselectivity ([2S, 4R]-[+]-trans > [2S, 4R]-[−]-trans), with absolute configuration confirmed by single X-ray crystallographic data for the 4-(4′-Cl)-PAT analog. Pharmacological affinity results and computational results herein support further PAT drug development studies and provide a basis for predicting and interpreting translational results, including, for (+)-trans-4-(4′-Cl)-PAT and (−)-trans-4-(3′-Br)-PAT that were previously shown to be more potent and efficacious than their corresponding enantiomers in rodent models of psychoses, psychostimulant-induced behaviors, and compulsive feeding (‘binge-eating’).

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Section: Pharmacological Characterizationsupporting

confidence: 91%

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

Sakhuja

Kondabolu

Córdova-Sintjago

et al. 2015

Bioorganic & Medicinal Chemistry

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“…To validate GPCR receptor models and associated ligand docking studies, experimental studies that measure ligand binding and function at wild type (WT) vs. point-mutated GPCRs are commonly employed. For example, modeling studies suggest ligand binding at serotonin 5-HT 2 and other aminergic neurotransmitter GPCRs is facilitated by a critical ionic interaction between a positively charged amine moiety of the ligand and the carboxylate of the fully-conserved aspartate residue D3.32 of the receptor [24–28]. Experimental validation of the proposed D3.32–ligand interaction at 5-HT 2C GCPRs recently was reported in studies involving mutation of the 5-HT 2C D3.32 residue to alanine (D3.32A), which abolished detectable binding of the 5-HT 2C radioligand [ 3 H]-mesulergine [29].…”

Section: Introductionmentioning

confidence: 99%

Aromatic interactions impact ligand binding and function at serotonin 5-HT_2CG protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

et al. 2013

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The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ~75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses, whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists—in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function, however, ligand interactions with these residues at the 5-HT2C receptor has not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modeling, ligand docking, and molecular dynamics (MD) simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

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“…Thus, it is known that ligand binding at serotonin 5-HT 2 and other monoaminergic GPCRs requires ionic interaction between a ligand positively charged amine moiety and the carboxylate of the fully conserved aspartate residue D3.32. [24–28] For example, we recently reported that mutation of D3.32 to alanine (D3.32A) in the 5-HT 2C GPCR abolishes detectable binding of the radioligand [ 3 H]-mesulergine. [29] This and other experimental results helped to validate ligand docking and molecular dynamics (MDs) results using a 5-HT 2C receptor model built by homology to the human β 2 AR.…”

Section: Introductionmentioning

confidence: 99%

Molecular determinants for ligand binding at serotonin 5‐HT_2A and 5‐HT_2C GPCRs: Experimental affinity results analyzed by molecular modeling and ligand docking studies

Córdova-Sintjago¹,

Sakhuja²,

Kondabolu³

et al. 2012

Int J of Quantum Chemistry

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Ligands that activate the serotonin 5-HT2C G protein-coupled receptor (GPCR) may be therapeutic for psychoses, addiction, and other neuropsychiatric disorders. Ligands that are antagonists at the closely related 5-HT2A GPCR also may treat neuropsychiatric disorders; in contrast, 5-HT2A activation may cause hallucinations. 5-HT2C-specific agonist drug design is challenging because 5-HT2 GPCRs share 80% transmembrane (TM) homology, same second messenger signaling, and no crystal structures are reported. To help delineate molecular determinants underlying differential binding and activation of 5-HT2 GPCRs, 5-HT2A, and 5-HT2C homology models were built from the β2-adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5-HT2 receptor models were conducted with the (2R, 4S)- and (2S, 4R)-enantiomers of the novel 5-HT2C agonist/5-HT2A/2B antagonist trans-4-phenyl-N,N-dimethyl-2-aminotetralin (PAT) and its 4′-chlorophenyl congners. Results indicate PAT–5-HT2 molecular interactions especially in TM domain V are important for the (2R, 4S) enantiomer, whereas, TM domain VI and VII interactions are more important for the (2S, 4R) enantiomer.

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Molecular determinants of ligand-directed signaling for the histamine H1 receptor

Cited by 9 publications

References 8 publications

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

Aromatic interactions impact ligand binding and function at serotonin 5-HT_2CG protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

Molecular determinants for ligand binding at serotonin 5‐HT_2A and 5‐HT_2C GPCRs: Experimental affinity results analyzed by molecular modeling and ligand docking studies

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Molecular determinants of ligand-directed signaling for the histamine H1 receptor

Cited by 9 publications

References 8 publications

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

Aromatic interactions impact ligand binding and function at serotonin 5-HT2CG protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

Molecular determinants for ligand binding at serotonin 5‐HT2A and 5‐HT2C GPCRs: Experimental affinity results analyzed by molecular modeling and ligand docking studies

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Aromatic interactions impact ligand binding and function at serotonin 5-HT_2CG protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

Molecular determinants for ligand binding at serotonin 5‐HT_2A and 5‐HT_2C GPCRs: Experimental affinity results analyzed by molecular modeling and ligand docking studies