SAR of SSRI

Case: Citalopram
 Presinaps
The Serotonin Pathway (Axon)
in Human Brain

Raphe nuclei

Sinaps Gap

Postsinaps
(Dendrit)

Charnay, Y., & Léger, L. (2010). Brain serotonergic

circuitries. Dialogues in clinical neuroscience, 12(4),
471–487.
Synthesis of
serotonin
Serotonin (5-HT) Receptors Distribution

Serotonin (5-HT) receptors in the human

brain: distribution, putative functions, and
related pathologies. Pre-RNA *splicing
and ° editing variants. For review see also
refs 98 to100. X, dorsal motor n of the
vagus nerve; ACN, accumbens n; Amy,
amygdala; cc, corpus callosum; Ce,
cerebellum; CPu, caudate-putamen; Cx,
cortex; DRN, dorsal raphe n; Fcx, frontal
cortex; Hip, hippocampus; Hyp,
hypothalamus; LS, lateral septum; MRN,
n, nucleus; SN, subtantia nigra; Tha,
thalamus; VTA, ventral tegmental area

Charnay, Y., & Léger, L. (2010). Brain serotonergic

circuitries. Dialogues in clinical neuroscience, 12(4), 471–487.
SERT Inhibitor: Citalopram
The effect of some substituents of citalopram against its biological response
It found that two of the four positions are main determinants for the biological activity

Fluorine
N-Methyl is less important in
Is less important in SERT inhibition
SERT inhibition

talopram

Methyl group The loss of cyanogroup and the presence of

The presence of methyl group in this site dimethyl lead to the lost of SERT inhibition

Cyanogroup decrease the activity of SERT inhibition

A major determinats for Andersen J, Kristensen AS, Bang-Andersen B, Strømgaard
enhancing SERT inhibition K. Recent advances in the understanding of the interaction
of antidepressant drugs with serotonin and norepinephrine
transporters. Chem Commun (Camb). 2009 Jul 7;
(25):3677-92. doi: 10.1039/b903035m. Epub 2009 May 7.
PMID: 19557250.
2009 Jul 7;(25):3677-92. doi: 10.1039/b903035m. Epub 2009 May 7. PMID: 19557250.
interaction of antidepressant drugs with serotonin and norepinephrine transporters. Chem Commun (Camb).
Andersen J, Kristensen AS, Bang-Andersen B, Strømgaard K. Recent advances in the understanding of the The stereochemistry of citalopram has great importance
in SERT inhibition

Escitalopram

(S) Enantiomer is 27-170 times more potent than (R) enantiomers. The escitalopram
inhibit SERT through allosteric sites. It makes escitalopram as a citalopram modulator in
SERT inhibition to enhance the inhibition of SERT.
Orthosteric vs Allosteric Sites of SERT
These effects are a combination of RESONANCE and INDUCTIVE effects. The
effects are also important in other reactions and properties (e.g. acidity of the
substituted benzoic acids).Here are some general pointers for recognising the
substituent effects:
 The H atom is the standard and is regarded as having no effect.
 Activating groups increase the rate
 Deactivating groups decrease the rate
 EDG = electron donating group
 EDG can be recognised by lone pairs on the atom adjacent to the π system,
eg: -OCH3
 except -R, -Ar or -vinyl (hyperconjugation, π electrons)
 EWG = electron withdrawing group
 EWG can be recognised either by the atom adjacent to the π system having
several bonds to more electronegative atoms, or, having a formal +ve or δ +ve
charge, eg: -CO2R, -NO2
 EDG / activating groups direct ortho / para
 EWG / deactivating groups direct meta
 except halogens (-X) which are deactivating BUT direct ortho / para
 EDG add electron density to the π system making it more nucleophilic
 EWG remove electron density from the π system making it less nucleophilic.
 SAR of Citalopram at Orthosteric Site

Citalopram

Has better activity

Citalopram
Zhang, P., Cyriac, G., Kopajtic, T., Zhao, Y., Javitch, J. A., Katz, J. L., & Newman, A. H. (2010). Structure-activity relationships for a novel
series of citalopram (1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile) analogues at monoamine
transporters. Journal of medicinal chemistry, 53(16), 6112–6121. https://doi.org/10.1021/jm1005034
SAR of Citalopram and its derivatives at Allosteric
Site

Table 1. Screening of allosteric effect of citalopram

analogues on [3 H]-SCIT dissociation

Larsen MA, Plenge P, Andersen J, Eildal JN, Kristensen AS, Bøgesø KP, Gether U,
Strømgaard K, Bang-Andersen B, Loland CJ. Structure-activity relationship studies of
citalopram derivatives: examining substituents conferring selectivity for the allosteric site
in the 5-HT transporter. Br J Pharmacol. 2016 Mar;173(5):925-36. doi: 10.1111/bph.13411.
Epub 2016 Feb 8. PMID: 26699847; PMCID: PMC4761100.
 SAR of Citalopram and its
derivatives at Allosteric Site

Table 2. IC50 values for [3 H]-S-CIT displacement and allosteric potency of S-CIT and the cyano-containing analogues