ArticleBritish journal of pharmacology2016
Structure-activity relationship studies of citalopram derivatives: examining substituents conferring selectivity for the allosteric site in the 5-HT transporter.
Article in British journal of pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 29 citations in OpenAlex.
- The Role of Small Molecules Containing Fluorine Atoms in Medicine and Imaging Applications.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Dynamic extracellular vestibule of human SERT: Unveiling druggable potential with high-affinity allosteric inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Applications and Potential of In Silico Approaches for Psychedelic Chemistry.Molecules (Basel, Switzerland) · 2023Review
- Persistent binding at dopamine transporters determines sustained psychostimulant effects.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Discovery and Development of Monoamine Transporter Ligands.Advances in neurobiology · 2023Review
- The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter.Nature communications · 2021Article
- Multitarget Approach to Drug Candidates against Alzheimer's Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets.Molecules (Basel, Switzerland) · 2020Article
- Monoamine transporters: structure, intrinsic dynamics and allosteric regulation.Nature structural & molecular biology · 2019Review
- Identification of the benztropine analog [Neurochemistry international · 2019Article
- Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs.Biochemical pharmacology · 2017Article
- Structure-activity relationship studies of citalopram derivatives: examining substituents conferring selectivity for the allosteric site in the 5-HT transporter.British journal of pharmacology · 2016Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThe 5-HT transporter (SERT) is a target for antidepressant drugs. SERT possesses two binding sites: the orthosteric (S1) binding site, which is the presumed target for current SERT inhibitors, and an allosteric (S2) site for which potential therapeutic effects are unknown. The antidepressant drug citalopram displays high-affinity S1 binding and low-affinity S2 binding. To elucidate a possible therapeutic role of allosteric inhibition of SERT, a drug that specifically targets the allosteric site is required. The purpose of this study was to find a compound having higher selectivity towards the S2 site. EXPERIMENTAL APPROACH: We performed a systematic structure-activity relationship study based on the scaffold of citalopram and the structurally closely related congener, talopram, which shows low-affinity S1 binding in SERT. The role of the four chemical substituents, which distinguish citalopram from talopram in conferring selectivity towards the S1 and S2 site, respectively, was assessed by determining the binding of 14 citalopram/talopram analogous to the S1 and S2 binding sites in SERT using membranes of COS7 cells transiently expressing SERT. KEY
resultsThe structure-activity relationship study revealed that dimethyl citalopram possesses the highest affinity for the allosteric site relative to the S1 site in SERT and has approximately twofold selectivity for the allosteric site relative to the S1 site in SERT. CONCLUSIONS AND IMPLICATIONS: The compound could be a useful lead for future synthesis of drugs with high affinity and high selectivity towards the allosteric binding site.
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