Escitalopram versus citalopram: the surprising role of the R-enantiomer

Sanchéz, Connie; Bøgesø, Klaus P.; Ebert, Bjarke; Reines, Elin Heldbo; Bræstrup, Claus

doi:10.1007/s00213-004-1865-z

Cited by 223 publications

(145 citation statements)

References 76 publications

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“…The Y95F mutant is the first substitution to impact stereospecific recognition of an inhibitor by SERT and could provide a critical tool in studying the fundamentals of citalopram-SERT interactions. More importantly, there are emerging data that allosteric modulation of (S)-CIT binding by the R-isomer may influence in vivo potency for uptake blockade by the racemic mixture (28,29). In contrast, the I172M mutation impacts the potency of both (R)-and (S)-CIT equivalently, suggesting that Ile-172 interacts with a region of citalopram that is not affected by isomerization, i.e.…”

Section: Discussionmentioning

confidence: 99%

Tyr-95 and Ile-172 in Transmembrane Segments 1 and 3 of Human Serotonin Transporters Interact to Establish High Affinity Recognition of Antidepressants

Henry

Field

Adkins

et al. 2006

Journal of Biological Chemistry

163

232

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In previous studies examining the structural determinants of antidepressant and substrate recognition by serotonin transporters (SERTs), we identified Tyr-95 in transmembrane segment 1 (TM1) of human SERT as a major determinant of binding for several antagonists, including racemic citalopram ((RS)-CIT). Here we described a separate site in hSERT TM3 (Ile-172) that impacts (RS)-CIT recognition when switched to the corresponding Drosophila SERT residue (I172M). The hSERT I172M mutant displays a marked loss of inhibitor potency for multiple inhibitors such as (RS)-CIT, clomipramine, RTI-55, fluoxetine, cocaine, nisoxetine, mazindol, and nomifensine, whereas recognition of substrates, including serotonin and 3,4-methylenedioxymethamphetamine, is unaffected. Selectivity for antagonist interactions is evident with this substitution because the potencies of the antidepressants tianeptine and paroxetine are unchanged. Reduced cocaine analog recognition was verified in photoaffinity labeling studies using [ 125 I]MFZ 2-24. In contrast to the I172M substitution, other substitutions at this position significantly affected substrate recognition and/or transport activity. Additionally, the mouse mutation (mSERT I172M) exhibits similar selective changes in inhibitor potency. Unlike hSERT or mSERT, analogous substitutions in mouse dopamine transporter (V152M) or human norepinephrine transporter (V148M) result in transporters that bind substrate but are deficient in the subsequent translocation of the substrate. A double mutant hSERT Y95F/ I172M had a synergistic impact on (RS)-CIT recognition (ϳ10,000-fold decrease in (RS)-CIT potency) in the context of normal serotonin recognition. The less active enantiomer (R)-CIT responded to the I172M substitution like (S)-CIT but was relatively insensitive to the Y95F substitution and did not display a synergistic loss at Y95F/ I172M. An hSERT mutant with single cysteine substitutions in TM1 and TM3 resulted in formation of a high affinity cadmium metal coordination site, suggesting proximity of these domains in the tertiary structure of SERT. These studies provided evidence for distinct binding sites coordinating SERT antagonists and revealed a close interaction between TM1 and TM3 differentially targeted by stereoisomers of CIT. SERT,2 like several other members of the SLC6A gene family, acts to remove neurotransmitter from the synapse following neurotransmission (1) and is a major target for treatment of mood disorders, including major depression, anxiety, post-traumatic stress, and obsessive-compulsive disorders (2). Agents that target SERT include tricyclic antidepressants and serotonin-specific reuptake inhibitors (SSRIs) that block 5HT binding and uptake. Despite its clinical significance, very little is understood concerning the structural aspects of SERT and how they relate to its function and antagonist recognition. The current data predict that SERT proteins are composed of 12 transmembrane-spanning segments, intracellular NH 2 and COOH termini and a large second extracellular...

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Section: Discussionmentioning

confidence: 99%

Tyr-95 and Ile-172 in Transmembrane Segments 1 and 3 of Human Serotonin Transporters Interact to Establish High Affinity Recognition of Antidepressants

Henry

Field

Adkins

et al. 2006

Journal of Biological Chemistry

163

232

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“…Anomalous dispersion effects were negligible and Friedel pairs were merged before re®nement. The absolute structure of (I) was assigned on the basis of the known chirality of escitalopram (Sanchez et al, 2004). The C-and N-bound H atoms were placed in idealized locations (CÐH = 0.95±0.99 A Ê and NÐH = 0.93 A Ê ) and re®ned as riding with U iso (H) values of 1.2U eq (carrier) or 1.5U eq (methyl C).…”

Section: Methodsmentioning

confidence: 99%

“…There are two C 20 H 22 FN 2 O + cations in the asymmetric unit; atoms C8 and C28 are assumed to possess S con®gura-tions, consistent with the known absolute structure of the biologically active enantiomer of citalopram (Sanchez et al, 2004). For the C1-containing molecule, the dihedral angle between the mean planes of the C2±C7 and C9±C14 benzene rings is 62.83 (13) , and the C1/C2/C7/C8/O1 ®ve-membered ring displays an envelope conformation with atom O1 in thē ap position [the displacement from the C-atom mean plane is 0.435 (5) A Ê ].…”

mentioning

confidence: 89%

Escitalopram oxalate: co-existence of oxalate dianions and oxalic acid molecules in the same crystal

et al. 2007

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“…Then concomitant psychiatric medication was withdrawn during the next 2 wk of treatment. Escitalopram was chosen as the antidepressive medication since the R-enantiomer present in citalopram has been suggested to reduce the efficacy of Senantiomer (escitalopram) which is mainly responsible for the serotonin reuptake inhibitory activity of the compound (Sánchez et al, 2004). The starting dose was 5 mg, which was increased in 5-mg steps every 1-2 wk, based on the clinical judgement of the investigators.…”

Section: Medicationmentioning

confidence: 99%

Antidepressive therapy with Escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients

Savaskan¹,

Mueller²,

Böhringer³

et al. 2008

European Psychiatry

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Depression is a common disorder in the elderly handicapping patients with affective and cognitive symptoms. Because of their good tolerability relative to the older tricyclic compounds, selective serotonin reuptake inhibitors (SSRIs) are increasingly used for the treatment of depression in the elderly. Little is known about their effects on cognition in elderly patients. In the present 4-week, single centre, randomized, open-label trial we investigated the anti-depressive effects of escitalopram, an SSRI, in 18 elderly depressed patients (mean age ±SEM: 76.2±1.8) compared to 22 healthy age-matched controls (mean age: 76.9±1.8). Affective and cognitive symptoms were assessed using the Geriatric Depression Scale (GDS), Mini-Mental State Examination (MMSE), and a face portrait recognition test to assess memory for happy and angry faces. Depressed patients prior to treatment had markedly reduced memory performance. Treatment with escitalopram improved affective and cognitive symptoms significantly. Furthermore, escitalopram treatment improved memory for negative facial stimuli. Control subjects confirmed the well established memory bias favouring recognition of identities acquired with happy expression. Importantly, this bias was absent in depressed patients prior, but also after treatment. In conclusion, escitalopram, even after a relatively short treatment period, was effective in treating depression in the elderly and may help improve cognitive performance for social stimuli.

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Escitalopram versus citalopram: the surprising role of the R-enantiomer

Abstract: The R-enantiomer present in citalopram counteracts the activity of the S-enantiomer, thereby providing a possible basis for the pharmacological and clinical differences observed between citalopram and escitalopram.

Cited by 223 publications

References 76 publications

Tyr-95 and Ile-172 in Transmembrane Segments 1 and 3 of Human Serotonin Transporters Interact to Establish High Affinity Recognition of Antidepressants

Tyr-95 and Ile-172 in Transmembrane Segments 1 and 3 of Human Serotonin Transporters Interact to Establish High Affinity Recognition of Antidepressants

Escitalopram oxalate: co-existence of oxalate dianions and oxalic acid molecules in the same crystal

Antidepressive therapy with Escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients

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