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The high-affinity binding site for tricyclic antidepressants resides in the outer vestibule of the serotonin transporter.

ABSTRACT: The structure of the bacterial leucine transporter from Aquifex aeolicus (LeuT(Aa)) has been used as a model for mammalian Na(+)/Cl(-)-dependent transporters, in particular the serotonin transporter (SERT). The crystal structure of LeuT(Aa) liganded to tricyclic antidepressants predicts simultaneous binding of inhibitor and substrate. This is incompatible with the mutually competitive inhibition of substrates and inhibitors of SERT. We explored the binding modes of tricyclic antidepressants by homology modeling and docking studies. Two approaches were used subsequently to differentiate between three clusters of potential docking poses: 1) a diagnostic SERT(Y95F) mutation, which greatly reduced the affinity for [(3)H]imipramine but did not affect substrate binding; 2) competition binding experiments in the presence and absence of carbamazepine (i.e., a tricyclic imipramine analog with a short side chain that competes with [(3)H]imipramine binding to SERT). Binding of releasers (para-chloroamphetamine, methylene-dioxy-methamphetamine/ecstasy) and of carbamazepine were mutually exclusive, but Dixon plots generated in the presence of carbamazepine yielded intersecting lines for serotonin, MPP(+), paroxetine, and ibogaine. These observations are consistent with a model, in which 1) the tricyclic ring is docked into the outer vestibule and the dimethyl-aminopropyl side chain points to the substrate binding site; 2) binding of amphetamines creates a structural change in the inner and outer vestibule that precludes docking of the tricyclic ring; 3) simultaneous binding of ibogaine (which binds to the inward-facing conformation) and of carbamazepine is indicative of a second binding site in the inner vestibule, consistent with the pseudosymmetric fold of monoamine transporters. This may be the second low-affinity binding site for antidepressants.

SUBMITTER: Sarker S

PROVIDER: S-EPMC4513247 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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The high-affinity binding site for tricyclic antidepressants resides in the outer vestibule of the serotonin transporter.

Sarker Subhodeep S Weissensteiner René R Steiner Ilka I Sitte Harald H HH Ecker Gerhard F GF Freissmuth Michael M Sucic Sonja S

Molecular pharmacology 20100909 6

The structure of the bacterial leucine transporter from Aquifex aeolicus (LeuT(Aa)) has been used as a model for mammalian Na(+)/Cl(-)-dependent transporters, in particular the serotonin transporter (SERT). The crystal structure of LeuT(Aa) liganded to tricyclic antidepressants predicts simultaneous binding of inhibitor and substrate. This is incompatible with the mutually competitive inhibition of substrates and inhibitors of SERT. We explored the binding modes of tricyclic antidepressants by h ...[more]

PMID: 20829432

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Project description:BackgroundMigraine, ranked as the 7th-highest specific cause of disability worldwide, has caused an enormous burden on the economy and society. Tricyclic antidepressant (TCA) is one of the most commonly drugs for migraine prevention. However, evidence about the efficacy and tolerability of TCAs in the prophylaxis of migraine in adults is somewhat confusing.MethodsA computerized literature search of the PubMed, Embase, Cochrane, and Web of Science databases from inception to July 2016 was conducted. We reviewed all randomized controlled trials that assigned adults with a clinical diagnosis of migraine to TCAs or other treatments (placebo or other antidepressants). Reduction in migraine frequency or index and response rates to treatment were defined as the efficacy outcomes. Rates of dropout due to adverse effects were defined as the tolerability outcomes.ResultsIn total 12 trials consisting of 1006 participants were identified: 9 trials compared TCAs with placebo, and the other 3 compared amitriptyline with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). A significant advantage of TCAs compared with placebo in the prevention of migraine in adults was observed (standardized mean difference [SMD] = -.75; 95% confidence interval [CI] = -1.05 to -.46; P?<?.00001). Participants receiving TCAs were more likely to experience an ?50% reduction in their headache burden than those receiving placebo (risk ratio [RR] =1.40; 95% CI = 0.89-2.20; P?=?.14). In addition, the efficacy between amitriptyline and SSRIs or SNRIs did not differ for migraine prevention in adults (SMD = -.01; 95% CI = -0.31 to 0.28; P?=?.94) based on the available limited trials. However, TCAs were less well tolerated than placebo (RR = 1.73; 95% CI = 1.00-2.99; P?=?.05) and SSRI or SNRI (RR = 2.85; 95% CI = 0.97-8.41; P?=?.06) on account of adverse events.ConclusionsThis research reveals that TCAs were more effective than placebo, but no more than SSRI or SNRI in ameliorating the headache burden in adults with migraine. However, TCAs appeared to be less tolerated than placebo and SSRIs or SNRIs for some side effects.

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The high-affinity binding site for tricyclic antidepressants resides in the outer vestibule of the serotonin transporter.

Publications

The high-affinity binding site for tricyclic antidepressants resides in the outer vestibule of the serotonin transporter.

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