citalopram escitalopram Lexapro
Carbonic anhydrase activators. The selective serotonin reuptake inhibitors fluoxetine, sertraline and citalopram are strong activators of isozymes I and II.

Casini A, Caccia S, Scozzafava A, Supuran CT.

Universita degli Studi di Firenze, Dipartimento di Chimica, Rm 188, Via della Lastruccia 3, I-50019 (Firenze), Sesto Fiorentino, Italy.

The selective serotonin reuptake inhibitors (SSRI) fluoxetine, sertraline and citalopram have been investigated for their ability to activate two carbonic anhydrase (CA) isozymes, hCA I and hCA II, in parallel with two standard activators for which the X-ray structure (in complex with isozyme II) has been resolved: histamine and phenylalanine. All three SSRI activated both isozymes with potencies comparable to that of the standards although the profile was different: for hCA I, best activators were fluoxetine and histamine, with citalopram and sertraline showing weaker activity. For hCA II, the best activators were phenylalanine and citalopram, and the weakest histamine and sertraline, whereas fluoxetine showed an intermediate behavior. These results suggest that SSRI efficacy in major depression complicating Alzheimer's disease may be partly due to their ability to activate CA isozymes and may lead to the development of potent activators for the therapy of diseases associated with significant decreases in brain CA activity.

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citalopram escitalopram Lexapro
[Mechanisms of action of antidepressants: new data from Escitalopram]

[Article in French]

Fabre V, Hamon M.

INSERM U288, Neuropsychopharmacologie, CHU Pitie-Salpetriere, 91, boulevard de l'Hopital, 75634 Paris cedex 13.

A first improvement in the treatment of depression was achieved in 1970-80 with the development of selective serotonin reuptake inhibitors (SSRI) because these drugs, which are as potent antidepressants as the tricyclics, are devoid of most of the secondary effects of the latter drugs (orthostatic hypotension, weight gain, dry mouth, etc, mainly caused by their capacity to block alpha1-adrenergic, H1 histaminergic and muscarinic receptors). However, SSRI did not solve all the problems inherent to the treatment of depression because (i) approximately 30% of depressed patients do not respond to these drugs, and (ii) their antidepressant effect becomes really significant only after 3-4 weeks of treatment, like that observed with tricyclics. A further improvement in the development of antidepressant drugs has recently been made with the synthesis of the S enantiomer of citalopram, called Escitalopram. Indeed, this active enantiomer is the most selective among all SSRI available to date, including citalopram. In addition, the potency of Escitalopram to inhibit serotonin reuptake (K(i)=2,1 nM) and to induce antidepressant-like effects in relevant animal paradigms (forced swimming test; chronic mild stress; stress-induced ultrasonic vocalization) is markedly increased as compared with citalopram and other SSRI. In particular, in the forced swimming test, which is especially relevant for assessing the potential antidepressant properties of drugs, Escitalopram was shown to be at least 15 fold more potent than any other SSRI to delay helplessness-induced immobility of rats. Even more interestingly, under chronic treatment conditions, Escitalopram was found to be significantly more rapid than any other antidepressant (tricyclics such as imipramine, SSRI such as fluoxetine) to restore sucrose intake in rats subjected to chronic mild stress, suggesting a reduced delay in its antidepressant action. This was indeed fully confirmed in humans as only 1-2 weeks of treatment with Escitalopram was enough to significantly reduce MADRS score in depressed subjects, compared to 3-4 weeks with any other antidepressant drug. These unique properties led to further investigations of the pharmacological profile of Escitalopram. It thus appeared that, at equipotent doses, the S enantiomer was significantly more efficient than citalopram (racemate) to increase the extracellular levels of serotonin within the frontal cortex of freely moving rats bearing a locally implanted microdialysis probe. Further experiments showed that R-citalopram counteracted the capacity of Escitalopram to enhance extracellular 5-HT levels, thereby explaining why the racemate had only a limited action in this regard. In addition, behavioural studies (stress-induced ultrasonic vocalization test) also showed that R-citalopram exerts effects opposite to those (antidepressant--and anxiolytic--like effects) of Escitalopram. The reason for these differences between the two enantiomers might concern the secondary molecular targets at which citalopram acts, but with affinities at least two orders of magnitude less than for the serotonin transporter. Indeed, R-citalopram has a 7-10-fold higher affinity for H1 histaminergic (K(i)=180 nM) and alpha1-adrenergic (K(i)=560 nM) receptors than Escitalopram (respective K(is) > or = 2 000 nM), and this difference might contribute not only to the better selectivity of the latter enantiomer for its therapeutically relevant target (i.e. the serotonin transporter) but also to its improved capacity to enhance central 5-HT neurotransmission. On the other hand, the global affinity of Escitalopram (K(i)=200-430 nM) for both subtypes of sigma receptors (sigma1 and sigma2) is higher than that of R-citalopram (and of the racemate citalopram; K(i)=200-1 500 nM), and this might also strengthen the antidepressant and anxiolytic effects of the S enantiomer because behavioural studies showed that selective sigma1 and sigma2 agonists are endowed with both antidepressant--and anxiolytic-like properties in relevant animal models. However, to date, the exact nature (agonist or antagonist) of the action of Escitalopram at sigma receptors is not known yet, and this question has to be addressed in future investigations. Altogether, these data open novel perspectives for both a better treatment of depressive disorders and a better knowledge of the neurobiological mechanisms underlying antidepressant therapy, and, possibly, depression itself.

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citalopram escitalopram Lexapro
Synthesis and biological evaluation of novel carbon-11-labelled analogues of citalopram as potential radioligands for the serotonin transporter.

Madsen J, Merachtsaki P, Davoodpour P, Bergstrom M, Langstrom B, Andersen K, Thomsen C, Martiny L, Knudsen GM.

PET & Cyclotron Unit 3982, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark. j.madsen rh.dk

Three serotonin reuptake inhibitors where the 5-cyano group in citalopram [1-(3-dimethylamino-propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1)] was replaced with a methyl, acetyl and piperidinyl carbonyl group, respectively, were synthesized. In a Stille reaction applying [(11)C]methyl iodide the labelled compound [5-methyl-(11)C][3-[1-(4-fluorophenyl)-5-methyl-1,3-dihydroisobenzofuran-1-yl]-propyl]-dimethylamine ([(11)C]-2) was synthesized in 60-90% radiochemical yield. [5-carbonyl-(11)C][1-[1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]-1-piperidin-1-yl-methanone] ([(11)C]-3) was synthesized in 62% radiochemical yield in a palladium mediated cross-coupling reaction utilizing [(11)C]carbon monoxide. The specific activity of [(11)C]-2 was highly dependent on whether the corresponding trimethyltin or tributyltin precursor was applied. In ex vivo rodent studies compound [(11)C]-2 exhibited a good blood-brain barrier (BBB) penetration whereas [(11)C]-3 did not. The brain distribution of [(11)C]-2 was investigated in a non-human primate using PET. There was a rapid uptake of radioactivity into the brain. Accumulation of the radiotracer was in agreement with the known distribution of serotonin transporters. The maximal thalamus to cerebellum ratio of 1.3 was reached after 85 min and the specific binding was partly blocked after pre-treatment with citalopram. Thus, [(11)C]-2 does not exhibit appropriate properties as radioligand for visualization of the serotonin transporter in vivo.

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citalopram escitalopram Lexapro
Antidepressant-like effects in various mice strains in the tail suspension test.

Ripoll N, David DJ, Dailly E, Hascoet M, Bourin M.

Faculte de Medecine, EA 3256 Neurobiologie de l'anxiete et de la depression, BP 53508, 1 rue Gaston Veil, F44035 Nantes, Cedex 01, France.

Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion.The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2mg/kg) and C57BL/6J Rj to paroxetine (from 0.5mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.

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citalopram escitalopram Lexapro
Enantiomeric separation of citalopram and its metabolites by capillary electrophoresis.

Mandrioli R, Fanali S, Pucci V, Raggi MA.

Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.

A simple and fast capillary electrophoretic method has been developed for the enantioselective separation of citalopram and its main metabolites, namely N-desmethylcitalopram and N,N-didesmethylcitalopram, using beta-cyclodextrin (beta-CD) sulfate as the chiral selector. For method optimisation several parameters were investigated, such as CD and buffer concentration, buffer pH, and capillary temperature. Baseline enantioseparation of the racemic compounds was achieved in less than 6 min using a fused-silica capillary, filled with a background electrolyte consisting of a 35 mM phosphate buffer at pH 2.5 supplemented with 1% w/v beta-CD sulfate and 0.05% w/v beta-CD at 25 degrees C and applying a voltage of -20 kV. A fast separation method for citalopram was also optimized and applied to the analysis of pharmaceutical formulations. Racemic citalopram was resolved in its enantiomers in less than 1.5 min using short-end injection (8.5 cm, effective length) running the experiments in a background electrolyte composed of a 25 mM citrate buffer at pH 5.5 and 0.04% w/v beta-CD sulfate at a temperature of 10 degrees C.

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citalopram escitalopram Lexapro
Molecular mechanism of citalopram and cocaine interactions with neurotransmitter transporters.

Ravna AW, Sylte I, Dahl SG.

Department of Pharmacology, Institute of Medical Biology, University of Tromso, Norway.

The selective serotonin reuptake inhibitors (SSRIs) and cocaine bind to the neural serotonin (5-HT) transporter (SERT) and thus inhibit presynaptic reuptake of 5-HT and elevate its concentration in the synaptic cleft. Cocaine also binds to the dopamine transporter (DAT) and to the noradrenaline transporter (NET) and inhibits presynaptic reuptake of dopamine and noradrenaline. SERT, DAT, and NET belong to the sodium/neurotransmitter symporter family, which is predicted to have a molecular structure with 12 transmembrane alpha-helices (TMHs) and intracellular amino- and carboxy terminals. We used an electron density projection map of the Escherichia coli Na+/H+ anti-porter, and site-directed mutagenesis data on DAT and SERT to construct 3-dimensional molecular models of SERT, DAT and NET. These models were used to simulate the molecular interaction mechanisms of the SSRI, S-citalopram, its less potent enantiomer, R-citalopram and of cocaine with the transporters. In the SERT model, a single amino acid (Tyr95) in TMH1 determined the transporter selectivity of S-citalopram for SERT over DAT and NET. A dipole-dipole interaction was formed between the hydroxy group of Tyr95 in SERT and the nitril group of S-citalopram, but could not be formed by S-citalopram in DAT and NET where the corresponding amino acid is a phenylalanine. The lower binding affinity of R-citalopram may be due to sterical hindrance at the binding site. The tropane ring of cocaine interacted with Tyr95 in SERT and with the corresponding phenylalanines in NET and DAT. This may explain why cocaine, but not S-citalopram, has high binding affinity to all three transporters.

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citalopram escitalopram Lexapro
R-citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety.

Sanchez C, Gruca P, Bien E, Papp M.

Neuropharmacological Research, H. Lundbeck A/S, Copenhagen-Valby, Denmark. cs lundbeck.com

S-citalopram (escitalopram) mediates the serotonin reuptake inhibitory effect of the racemate, R,S-citalopram. The effect of escitalopram (0.5-3.9 mg/kg) was investigated in a rat conditioned fear stress model of anxiety and compared to the effects of R-citalopram (1.0-7.8 mg/kg), R,S-citalopram (4.0 and 8.0 mg/kg), and escitalopram (2.0 mg/kg)+R-citalopram (7.8 mg/kg). Diazepam (0.95 mg/kg) and buspirone (4.6 mg/kg) were included as positive controls. During an acquisition session, rats were allowed to freely explore a novel cage for 9 min. During that time, they received two inescapable footshocks through an electrifiable grid floor. Groups of nonshocked control rats were run in parallel. During an expression session on the next day, rats were treated with drug or vehicle 30 min before they were reintroduced into the test cage for a 9-min period this time without receiving footshocks and the total distance travelled was recorded. The distance travelled by vehicle-treated rats was markedly suppressed compared to a vehicle-treated group of nonshocked controls. Escitalopram produced a dose-dependent inhibition of the conditioned suppression of exploratory behaviour (minimal effective dose 1.0 mg/kg). Interestingly R,S-citalopram 4.0 and 8.0 mg/kg produced significantly smaller effect than escitalopram 2.0 and 4.0 mg/kg, receptively. R-citalopram, 7.8 mg/kg, produced a significant effect. However, in spite of this, R-citalopram (7.8 mg/kg) significantly inhibited the effect of escitalopram (2.0 mg/kg). The activity in drug-treated nonshocked groups was similar to the vehicle-treated group, except for the buspirone-treated group where a significant reduction was observed. The finding that R-citalopram inhibits the effect of escitalopram may be relevant to the improved clinical efficacy seen with escitalopram compared to R,S-citalopram in the treatment of anxiety and depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12957234&dopt=Abstract citalopram escitalopram Lexapro