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Serotonin transporters inhibitors

BMS-505130 (7) is a potent and selective serotonin transporter inhibitor (SERT K< = 0.18 nM, NET K< — 4.6 gM, DAT K< — 2.1 (tM). In brain microdialysis studies, 7 demonstrated a dose-dependent increase in cortical serotonin levels. Compound 7 was also active in the mouse tail suspension model [15]. Following oral administration, peak plasma concentration of 7 was reached at 1.6 h and then declined to a concentration less than 10% of Cmax within 6 h. The short half-life of 7 might be advantageous for the treatment of PE where an acute effect to delay ejaculation followed by a relatively rapid fall in SSRI plasma concentration might be desirable. [Pg.15]

Based on existing findings, there are many important hypotheses in pediatric psychopharmacogenetics. Selective serotonin transporter inhibitors have been shown to have efficacy in double-blind studies in children and/ or adolescents in the treatment of autism, major depression, OCD, and anxiety disorders. Given the association of the serotonin transporter promoter variant with SSRI treatment response in adult depression (Smeraldi et ah, 1998), all of the SSRI-responsive phenotypes should be tested for promoter variant influence on response using family-based or population-based controlled association studies. The report of strong 5-HTTLPR allelic effects on SSRI-induced mania (Mundo et ah, 2000) is of special interest given frequent SSRI-induced activation in children. [Pg.92]

Greist, J.H., Jefferson, J.W, Kobak, K.A., Katzelnick, D.J., and Ser-lin, R.C. (1995) Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis [see comments]. Arch Gen Psychiatry 52 53-60. [Pg.442]

Chen, F., Larsen, M.B., Sanchez, C., and Wiborg, O. 2005. The 5-enantiomer of R,5-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. Eur. Neuropsychopharmacol. 15 193-198. [Pg.362]

MDMA overdose as well as the concomitant consumption of selective serotonin reuptake inhibitors (SSRI) with other dmgs that exert serotoninergic effects (such as inhibitors of monoamine oxidase) can rapidly lead to the serotonin syndrome. Its symptoms, which are reversible upon cessation, of the drug include confusion, muscle rigidity in the lower limbs, and hyperthermia suggesting an acute reaction to serotonin overflow in the CNS. Blocking the function of SERT outside the brain causes side effects (e.g., nausea), which may be due to elevated 5HT however , impairment of transporter function is not equivalent to direct activation of 5HT recqrtors in causing adverse effects such as fibrosis and pulmonary hypertension. [Pg.841]

Selective serotonine reuptake inhibitor (SSRI) is an abbreviation for the class of antidepressants known as the Selective Serotonin Reuptake Inhibitors. Examples of SSRIs include fluoxetine, paroxetine, citalopram, and sertraline. These drugs selectively inhibit the serotonin transporter thus prolonging the synaptic lifespan of the neurotransmitter serotonin. [Pg.1113]

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. [Pg.1124]

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. [Pg.1282]

Schuldiner, S (1998) Vesicular neurotransmitter transporters. In Neurotransmitter Transporters Structure, Function, and Regulation (Ed. Reith, MEA), Humana Press, Totowa, NJ, pp. 215-240. Stanford, SC (1995) Central noradrenergic neurones and stress. Pharmac. Ther. 68 297-342. Stanford, SC (1999) SSRI-induced changes in catecholaminergic transmission. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future (Ed. Stanford, SC), RG Landes Co., Austin, TX, pp. 147-170. [Pg.186]

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). [Pg.195]

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. [Pg.34]

The answer is d. (Kai ung, p 505.) Fluoxetine is a highly selective serotonin re uptake inhibitor (55RI) acting on the 5-1 IT transporter. It forms an active metabolite that is effective for several days. Selective serotonin reuptake inhibitors are inhibitors of cytochrome P450 isoenzymes, which is the basis of potential drug-drug interactions... [Pg.162]

Some failures will be due to the presence of variants in drug handling. Patients who are rapid acetylators of isoniazid have a slower antituberculous response than slow acetylators (Evans and Clarke, 1961). Asthmatics who do not respond well to (32-agonist bronchodilators may have fewer functioning p2-adrenergic receptors (Drysdale et al., 2000). Variations in the synthesis or structure of the serotonin transporter protein, which is involved in selective reuptake of serotonin by presynaptic neurons, may explain why some patients with depressive disorders respond to selective serotonin reuptake inhibitors and others do not (Steimer et al., 2001). [Pg.167]

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). [Pg.13]

Billett EA, Richter MA, King N, Heils A, Lesch KP, Kennedy JL (1997) Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Mol Psychiatry 2 403-406... [Pg.171]

Ramamoorthy S, Leibach FH, Mahesh VB, Ganapathy V (1993) Partial purification and characterization of the human placental serotonin transporter. Placenta 14 449-461 Rasmussen BB, Brosen K (2000) Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors Ther DrugMonit 22 143-154... [Pg.544]

Serotonin is removed from the synapse by a high-affinity serotonin uptake site [(4) in Fig. 2.6] that is capable of transporting serotonin in either direction, depending on its concentration. The serotonin transporter is blocked by selective serotonin reuptake inhibitors (SSRls) as well as by tricyclic antidepressants. [Pg.27]

Hirano, Kazufumi, Ryohei Kimura, Yumi Sugimoto, Jun Yamada, Shinya Uchida, Yasuhiro Kato, Hisakuni Hashimoto, and Shizuo Yamada. Relationship Between Brain Serotonin Transporter Binding, Plasma Concentration and Behavioural Effect of Selective Serotonin Reuptake Inhibitors. British Journal of Pharmacology 144 (2005) 695-702. The researchers show that SSRIs begin to act on serotonin transporters within hours. [Pg.102]

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... [Pg.652]


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See also in sourсe #XX -- [ Pg.398 , Pg.398 ]

See also in sourсe #XX -- [ Pg.398 , Pg.398 ]




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Serotonin transporter transporters

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