TY - JOUR
T1 - N-methyl-citalopram
T2 - A quaternary selective serotonin reuptake inhibitor
AU - Bismuth-Evenzal, Yona
AU - Roz, Netta
AU - Gurwitz, David
AU - Rehavi, Moshe
PY - 2010/11/15
Y1 - 2010/11/15
N2 - We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [3H]citalopram and uptake studies with [3H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10-7M as well as [3H]ketanserin binding to rat brain membranes at 10-5M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs.
AB - We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [3H]citalopram and uptake studies with [3H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10-7M as well as [3H]ketanserin binding to rat brain membranes at 10-5M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs.
KW - Cardiovascular diseases
KW - Citalopram
KW - Human serotonin transporter
KW - Platelets
KW - SLC6A4
KW - SSRI
UR - http://www.scopus.com/inward/record.url?scp=77957018253&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2010.07.035
DO - 10.1016/j.bcp.2010.07.035
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C2 - 20696140
AN - SCOPUS:77957018253
SN - 0006-2952
VL - 80
SP - 1546
EP - 1552
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 10
ER -