Desipramine transporters

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Noradrenaline transporters (NAT) are localized in the presynaptic plasma membrane of adrenergic nerve terminals. They belong to a family of proteins with 12 putative transmembrane proteins which are responsible for recycling of released neurotransmitters (noradrena-line/adrenaline, dopamine, serotonin, amino acid transmitters) back into the presynaptic nerve ending. Noradrenaline transporters can be blocked by a number of different antidepressant drags, including tricyclic antidepressants (e.g. desipramine) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). 

Szot, R, Ashliegh, E. A., Kohen, R. etal. (1993). Norepinephrine transporter mRNA is elevated in the locus coeruleus following short- and long-term desipramine treatment. Brain Res., 618, 308-12. 

Figure 7.15 Kinetics of transport across a filter-immobilized artificial membrane (a) desipramine and (b) dihydromethysticin concentrations in acceptor well. [Reprinted from Avdeef, A., in van de Waterbeemd, H. Lennemas, H. Artursson, R (Eds.). Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability. Wiley-VCH Weinheim, 2003 (in press), with permission from Wiley-VCH Verlag GmbH.]...

Reboxetine is the only selective and reasonably potent noradrenaline reuptake inhibitor available clinically at the present time. Reboxetine has a chemical structure not dissimilar from viloxazine, an antidepressant which was of only limited clinical interest in the 1970s because of its weak efficacy and unacceptable side effects (nausea, vomiting and occasionally seizures). Unlike the secondary amine TCA antidepressants, such as maprotiline, desipramine, nortriptyline and protriptyline, reboxetine does not affect any other transporter or receptor system and therefore is largely devoid of TCA and SSRI-like side effects. In clinical trials, reboxetine has been shown to be as effective as the SSRIs in the... 

Norepinephrine is removed from the synapse by means of two mechanisms. In the hrst, catechol-O-methyl-transferase (COMT) degrades intrasynaptic NE. In the second, the norepinephrine transporter (NET), a Na /CH-dependent neurotransmitter transporter, is the primary way of removing NE from the synapse [(4) in Fig. 2.7]. The NET is blocked selectively by desipramine and nortriptyline. Once internalized. 

The tertiary amine tricyclics have similar effects on norepinephrine and serotonin transmission, while the two secondary amines have more specific effects on norepinephrine, with much smaller effects on serotonin. This can be seen in the fCj (inhibitory constant) values for the TCAs, as listed in Table 23.1. is the concentration of drug required to block transport of the neurotransmitter (in this case, norepinephrine or serotonin). Lower fCj equals greater relative ability to block transport. Desipramine and NT have the greatest inhibitory effects at the receptor site, while CMI has... 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

Resistance to chloroquine is now very common among strains of P falciparum and uncommon but increasing for P vivax. In P falciparum, mutations in a putative transporter, PfCRT, have been correlated with resistance. Chloroquine resistance can be reversed by certain agents, including verapamil, desipramine, and chlorpheniramine, but the clinical value of resistance-reversing drugs is not established. 

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). 

Apparsundaram S, Schroeter S, Giovanetti E, Blakely RD (1998b) Acute regulation of norepinephrine transport II. PKC-modulated surface expression of human norepinephrine transporter proteins. J Pharmacol Exp Ther 287 744-751 Arndt lO, Dorozynsky L, Woody GE, McLeUan AT, O Brien CP (1992) Desipramine treatment of cocaine dependence in methadone-maintained patients. Arch Gen Psychiatry 49 888-893 Balkovetz DP, Tiruppathi C, Leibach PH, Mahesh VB, Gtmapathy V (1989) Evidence for an imipramine-sensitive serotonin transporter in humtm placenttil bmsh-border membranes. J Biol Chem 264 2195-2198... 

Gainetdinov RR, Caron MG (2003) Monoamine transporters from genes to behavior. Annu Rev Pharmacol Toxicol 43 261-284. Epub %2002 Sep 17 Garcia AS, Barrera G, Burke TF, Ma S, Hensler JG, Moiilak DA (2004) Autoreceptor-mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment. J Neurochem 91 683-693 Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56 33-39... 

Levin FR, Lehman AF (1991) Meta-analysis of desipramine as an adjunct in the treatment of cocaine addiction. J Clin Psychopharmacol 11 374-378 Lin Z, Madras BK (2006) Human genetics and pharmacology of neurotransmitter transporters. 

Since dopamine is inactivated by norepinephrine reuptake in trontal cortex, fl/hich largely lacks dopamine transporters, desipramine can thus increase dopamine neurotransmission in this part ot the brain... 

Noradrenaline is transported by uptake systems that have been extensively studied. On release of noradrenaline from sympathetic nerve varicosities in the peripheral nervous system, it is subject to two uptake systems. Uptake 1 (UJ is a reuptake process where the noradrenaline is recovered by the nerve via a process that has a high affinity but relatively low maximum rate, whereas a second process, uptake 2 (Uj), clears noradrenaline from the tissues into extraneuronal sites by a low affinity, but fast, process (which is inhibited by GLUCOCORTICOIDS, phenoxybenzamine and normetanephrine). The first - the neuronal system - has been studied in detail, and is essentially the same process as used for dopamine and 5-hydroxytryptamine in the CNS. The U transport protein has now been cloned, and is one of a famiiy of transporter proteins which act as co-transporters for Na, Cl and the amine, driven by the ATP-generated electrochemical gradient for Na . This Ui noradrenaline reuptake process is inhibited by cocaine and amphetamine (thus accounting for some of their actions, particularly within the CNS), phenoxybenzamine and the extensive class of tricyclic and related compounds that are used as ANTIDEPRESSANTS (e.g. desipramine). 

Cocaine inhibits the transporters for norepinephrine, serotonin, and dopamine. Binding of cocaine to the dopamine transporter Inhibits reuptake of dopamine, thus prolonging signaling at key brain synapses indeed, the dopamine transporter Is the principal brain cocaine receptor. Therapeutic agents such as the antidepressant drugs fluoxetine (Prozac) and imipramlne block serotonin uptake, and the tricyclic antidepressant desipramine blocks norepinephrine uptake. I... 

Protriptyline exhibits high selectivity for the NE transporter, but with less potenoy than desipramine. Its mechanism of action is similar to that of desipramine. Minimal effect on 5-HT reuptake has been observed. 

The affinity data for the SSRIs show that the SSRIs, as a group, are very potent and selective inhibitors for SERT compared with their affinity for NE and dopamine reuptake transporters (Fig. 21.6) and are more potent inhibitors of 5-HT reuptake than are the tertiary amine TCAs, with the exoeption of clomipramine. None of the SSRIs has substantial effeot on the NET or dopamine transporter. Of the SSRIs, sertraline exhibits the most potent inhibition of dopamine reuptake transporter, although it is still 100 times less potent in terms of inhibiting the dopamine versus the SERT. Therefore, the plasma oonoentration of sertraline would have to be increased by as much as 100 times to inhibit the dopamine reuptake transporter. When drugs are this selective for the reuptake transporters, differences in potency become olinioally irrelevant, because the plasma concentration oan be dose-adjusted to achieve inhibition of the desired transporter without affecting the other transporters. Clomipramine displays less affinity for SERT than oitalopram, fluvoxamine, paroxetine, or sertraline does and is more potent than fluoxetine. In terms of the ability to inhibit the NET, the SSRIs are two to three times less potent than the SNRI TCA, desipramine. 

Their in vitro potenoy for selectively inhibiting the 5-HT transporter more or less mirrors their clinical efficacy as SSRIs (11) paroxetine> sertraline> clomipramine> fluoxetine> citralopram> fluvoxamine> imipramine> amitriptyline> roboxetine> venlafaxine = milnacipran> desipramine. Clinically, however, all the SSRIs are equally effective over time, suggesting that these variations in potency do not affect efficacy or adverse effects. The SSRIs have less affinity for ai, 02, Hi, and musoarinic receptors, which may explain the adverse-effect profile differences between TCAs and SSRIs. 

Figure 15.6. (A) Correlation between human GIT and Caco-2 permeabihty. GIT permeability values are from Refs. [61-63]. Compounds included in the study are amUoride, antipyrine, amoxicMn, atenolol, carbamazepine, cimetidine, desipramine, furosemide, hydrochlorothiazide, ketoprofen, metoprolol, naproxen, piroxicam, propranolol, and ranitidine. (B) Correlation between human GI permeabihty and artificial membrane permeabihty (hexadecane artificial membrane). Paracehular transported compounds are given in bold.

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