ArticleThe Journal of pharmacology and experimental therapeutics2013
Molecular pharmacology and ligand docking studies reveal a single amino acid difference between mouse and human serotonin 5-HT2A receptors that impacts behavioral translation of novel 4-phenyl-2-dimethylaminotetralin ligands.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- 5-HTPharmacological reviews · 2025Review
- Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-ACS chemical neuroscience · 2024Article
- Psilocybin desynchronizes the human brain.Nature · 2024Article
- Identification of 5-HTNature communications · 2023Article
- "Selective" serotonin 5-HTBiochemical pharmacology · 2022Review
- Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity.Biochemistry · 2022Review
- Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice.Epilepsy research · 2021Article
- The synthetic cathinone psychostimulant α-PPP antagonizes serotonin 5-HTDrug testing and analysis · 2019Article
- Ligand-directed serotonin 5-HTEuropean journal of pharmacology · 2019Article
- Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics.Frontiers in pharmacology · 2018Review
- Discovery of new GPCR ligands to illuminate new biology.Nature chemical biology · 2017Article
- The serotonin 5-HTJournal of psychopharmacology (Oxford, England) · 2017Review
- Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.Naunyn-Schmiedeberg's archives of pharmacology · 2017Article
- Article
- Species-specific action of (Pro3)GIP - a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors.British journal of pharmacology · 2016Article
- Targeting Serotonin 5-HTAggression and violent behaviorArticle
- Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action.Handbook of experimental pharmacologyArticle
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
During translational studies to develop 4-phenyl-2-dimethylaminotetralin (PAT) compounds for neuropsychiatric disorders, the (2R,4S)-trans-(+)- and (2S,4R)-trans-(-)-enantiomers of the analog 6-hydroxy-7-chloro-PAT (6-OH-7-Cl-PAT) demonstrated unusual pharmacology at serotonin (5-HT) 5-HT2 G protein-coupled receptors (GPCRs). The enantiomers had similar affinities (Ki) at human (h) 5-HT2A receptors (≈ 70 nM). In an in vivo mouse model of 5-HT2A receptor activation [(±)-(2,5)-dimethoxy-4-iodoamphetamine (DOI)-elicited head twitch], however, (-)-6-OH-7-Cl-PAT was about 5-fold more potent than the (+)-enantiomer at attenuating the DOI-elicited response. It was discovered that (+)-6-OH-7-Cl-PAT (only) had ≈ 40-fold-lower affinity at mouse (m) compared with h5-HT2A receptors. Molecular modeling and computational ligand docking studies indicated that the 6-OH moiety of (+)- but not (-)-6-OH-7-Cl-PAT could form a hydrogen bond with serine residue 5.46 of the h5-HT2A receptor. The m5-HT2A as well as m5-HT2B, h5-HT2B, m5-HT2C, and h5-HT2C receptors have alanine at position 5.46, obviating this interaction; (+)-6-OH-7-Cl-PAT also showed ≈ 50-fold lower affinity than (-)-6-OH-7-Cl-PAT at m5-HT2C and h5-HT2C receptors. Mutagenesis studies confirmed that 5-HT2A S5.46 is critical for (+)- but not (-)-6-OH-7-Cl-PAT binding, as well as function. The (+)-6-OH-7-Cl-PAT enantiomer showed partial agonist effects at h5-HT2A wild-type (WT) and m5-HT2A A5.46S point-mutated receptors but did not activate m5-HT2A WT and h5-HT2A S5.46A point-mutated receptors, or h5-HT2B, h5-HT2C, and m5-HT2C receptors; (-)-6-OH-7-Cl-PAT did not activate any of the 5-HT2 receptors. Experiments also included the (2R,4S)-trans-(+)- and (2S,4R)-trans-(-)-enantiomers of 6-methoxy-7-chloro-PAT to validate hydrogen bonding interactions proposed for the corresponding 6-OH analogs. Results indicate that PAT ligand three-dimensional structure impacts target receptor binding and translational outcomes, supporting the hypothesis that GPCR ligand structure governs orthosteric binding pocket molecular determinants and resulting pharmacology.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.