Norepinephrine transporter inhibitors

The role of norepinephrine in the actions of stimulants has largely been overlooked, although a few studies suggest that this transmitter may be of major significance. On the other hand, until clinical studies are carried out using receptor blockers and specific norepinephrine transporter inhibitors, this area will remain muddy, at best. In virtually every... 

Figure 15.11 depicts an SAS map for a set of 299 norepinephrine transporter inhibitors (44,551 data points). In the figure (cf. Figure 15.10b), the ordinate indicates... 

Therefore, dopamine transporter inhibitors exhibit less effect in the FC. There, dopamine seems to be reuptaken by the norepinephrine transporter, which dopamine actually has a higher affinity for than norepinephrine itself. 

Although there is structural homology among the transporters for 5-HT, norepinephrine and dopamine, some drugs exhibit great selectivity at inhibiting the activity of just one of these proteins. For example, the selective norepinephrine re-uptake inhibitor reboxetine is 150 times more potent at inhibiting norepinephrine transport... 

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). 

Pharmacology Atomoxetine is a selective norepinephrine reuptake inhibitor. The precise mechanism by which it produces its therapeutic effects in ADHD is unknown, but it is thought to be related to selective inhibition of the presynaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. Pharmacokinetics ... 

Venlafaxine is a potent inhibitor of serotonin reuptake and a weaker inhibitor of norepinephrine transport such that at lower therapeutic doses it behaves like an SSRI. At high doses (more than 225 mg/d) it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine reuptake inhibition. Doses in the range of 300 mg/d or greater may confer broader therapeutic effects than SSRIs, but a careful titration up to these doses is needed to control adverse effects. 

Chaplin L, Cohen AH, Huettl P, Kennedy M, Njus D, Temperley SJ (1985) Reserpic acid as an inhibitor of norepinephrine transport into chromaffin vesicle ghosts. J Biol Chem 260 10981-10985. 

NE molecules released into the synaptic space are reabsorbed back into the presynaptic neuron by the membrane NE transporter (NET). This process requires ATP. The NET is a target for numerous drugs. Several tricyclic antidepressants (TCA), such as imipramine, non-specifically inhibit both NET and 5-HT (5-HTT) transporters (Corrodi and Fuxe 1968). Other TCAs, called norepinephrine reuptake inhibitors (NRIs), such as desipramine, specifically inhibit the NET (Curet et al., 1992 Lacroix et al., 1991). There are also non-tricyclic selective inhibitors of the NET, called selective norepinephrine reuptake inhibitors (SNeRIs), and dual inhibitors of the NET and 5-HTT (SNRIs). The examples for SneRIs and SNRIs are reboxetine and venlafaxine, respectively (Beique et al., 1998a Beique et al., 1998b Beique et al., 1999 Dawson et al., 1999 Szabo and Blier 2001c). 

Reuptake Norepinephrine transporter Tricyclic antidepressants (imipramine, f) Tricyclic norepinephrine reuptake inhibitors (desipiamine, ) Selective norepinephrine reuptake inhibitors (reboxetine, ) Dual serotonin/ norepinephrine reuptake inhibitors (venlafaxine, J.)... 

There are two principal mechanisms for increasing synaptic monoamine levels. One is to block the reuptake of neurotransmitter after its excitation-coupled release from the neuronal terminal. Thus, blocking the action of the uptake carrier protein prevents clearance of the neurotransmitter from the synapse, leaving high concentrations in the synaptic cleft that can continue to exert a signaling effect. This mechanism is the one invoked to explain the action of cocaine, a potent inhibitor of monoamine reuptake at the dopamine, serotonin, and norepinephrine transporters, and of methylphenidate, which is a reuptake inhibitor at the dopamine and norepinephrine transporters (81)It should be noted, however, that methylphenidate also has the ability to induce the release of catecholamines stored in neuronal vesicles (82, 83). 

A Rde for Norepinephrine. Although the vast majority of studies of psychostimulants have focused on the role of dopamine and/or serotonin, the importance of norepinephrine (thought to be paramount 30 years ago) is generally now overlooked. Details of the mechanism of action of psychostimulants have been developed primarily through the use of animal models, in which dopamine seems to be the key player, and these results then have been extrapolated to humans. Yet, cocaine also is a potent NE uptake inhibitor, and the potency of amphetamine for norepinephrine release is similar to that for dopamine release. Indeed, in the rat prefrontal cortex, amphetamine and cocaine increased extracellularnorepinephrine to an extent that was quantitatively similar to that of dopamine (116).Further, it appeared that the increase in prefrontal cortical norepinephrine was actually attributable to the blockade of the norepinephrine transporter by both drugs. Recently, Rothman et al. (117) reported that the oral doses of several stimulants required to produce amphetamine-like subjective effects in humans were most closely correlated with... 

Venlafaxine is a potent reuptake inhibitor of serotonin, with a less potent effect on norepinephrine and dopamine, and does not interact with other neurotransmitter receptors. The lower affinity for norepinephrine transport requires dose elevation in order to achieve both serotonin and norepinephrine inhibition. Emerging evidence indicates that higher doses of venlafaxine (200-375 mg/day) may have a faster onset of action, observed as early as 4 days to 1 week following treatment initiation. 

Moderate affinity for the specific receptor/transporter NARI Selective noradrenaline (norepinephrine) reuptake inhibitor... 

Amine uptake blockade The drugs that block norepinephrine transporters in the CNS (eg, tricyclics) also inhibit the reuptake of norepinephrine at nerve endings in the autonomic nervous system. Likewise, MAO inhibitors increase NE in sympathetic nerve terminals. In both cases, this can lead to peripheral autonomic sympathomimetic effects. However, longterm use of MAOIs can decrease blood pressure. 

Olivier B, Soudjin W, van Wijngaarden I. Serotonin, dopamine, and norepinephrine transporters in the CNS and their inhibitors. In Jucker E, ed. Progress in Drug Research, vol 54. Basel, Switzerland Birkhauser-Verlag, 2000 59-120. 

Serotonin also affects the emotions of love and romance. Androgens, estrogens, oxytocin, and vasopressin increase the sex drive, whereas increased levels of synaptic serotonin, such as result from the taking of reuptake transporter inhibitors, suppress the sex drive and inhibit feelings of attraction by the opposite sex. Dopamine and norepinephrine increase the sex drive. 

---