TY - JOUR

T1 - Structure-activity relationship studies of citalopram derivatives

T2 - examining substituents conferring selectivity for the allosteric site in the serotonin transporter

AU - Larsen, M Andreas B

AU - Plenge, Per

AU - Andersen, Jacob

AU - Eildal, Jonas Nii Nortey

AU - Kristensen, Anders S

AU - Bøgesø, Klaus P

AU - Gether, Ulrik

AU - Strømgaard, Kristian

AU - Bang-Andersen, Benny

AU - Loland, Claus J

N1 - This article is protected by copyright. All rights reserved.

PY - 2016/3

Y1 - 2016/3

N2 - BACKGROUND AND PURPOSE: The serotonin transporter (SERT) is 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 bearing 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, that 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 RESULTS: The structure-activity relationship study revealed a di-methyl citalopram, which binds to the S1 site with an affinity of 6.4 [4.7;8.8] μM (mean[SEM interval]) and shows an allosteric potency of 3.6 [3.3;3.8] μM, thus bearing ~2-fold 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. This article is protected by copyright. All rights reserved.

AB - BACKGROUND AND PURPOSE: The serotonin transporter (SERT) is 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 bearing 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, that 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 RESULTS: The structure-activity relationship study revealed a di-methyl citalopram, which binds to the S1 site with an affinity of 6.4 [4.7;8.8] μM (mean[SEM interval]) and shows an allosteric potency of 3.6 [3.3;3.8] μM, thus bearing ~2-fold 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. This article is protected by copyright. All rights reserved.

U2 - 10.1111/bph.13411

DO - 10.1111/bph.13411

M3 - Journal article

C2 - 26699847

VL - 173

SP - 925

EP - 936

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -