Norepinephrine uptake

Javitch, J.A. Blaustein, R.O. and Snyder, S.H. [ HjMazindol binding associated with neuronal dopamine and norepinephrine uptake sites. 

Serotonin uptake sites Norepinephrine uptake sites D-1 dopamine receptors Cholme uptake... 

MPTP, into dopamine neurons seems to be essential, and blockade of that aeeumulation prevents the neurotoxieity. MPP+ also ean be transported into norepinephrine neurons (Javitch et al. 1985), leading to neurotoxicity toward cortical norepinephrine neurons, an effect blocked by inhibitors of the norepinephrine uptake carrier (Sundstrom and Jonsson 1985). 

For example, in regions densely innervated by noradrenergic fibers, PCP is a very potent inhibitor of norepinephrine uptake. 

In the context of preparing benzothienyloxy phenylpropanamines as inhibitors of serotonin and norepinephrine uptake, a group from Eli Lilly and Company has developed a two-step synthesis of benzo[fo]thiophenes (Scheme 6.193) [354]. Thus, a 2-mercapto-3-phenylpropenoic acid derivative was cyclized with iodine in 1,2-dimethoxyethane at 120 °C to give 5-fluoro-4-methoxybenzothiophene-2-carboxylic acid in 67% yield. Decarboxylation under strongly basic conditions involving 1,8-di-azabicyclo[5.4.0]undec-7-ene (DBU) as base in N,N-dimethylacetamide (DMA) as... 

Which of the following is an antidepressant agent that selectively inhibits serotonin (5-HT) uptake with minimal effect on norepinephrine uptake ... 

The answer is c. (Hardman, p 436.) The tricyclics and second-generation antidepressants act by blocking serotonin or norepinephrine uptake into the presynaptic terminal. Fluoxetine selectively inhibits serotonin uptake with minimal effects on norepinephrine uptake. Protriptyline, maprotiline, desipramine, and amoxapine have greater effect on norepinephrine uptake... 

DeJong, A. P., Fesik, S. W., and Makriyannis, A. (1982) Conformational requirements for norepinephrine uptake by phenethylamines in brain synaptosomes. Effects of a-alkyl substitution. J. Med. Chem., 25 1438—1441. 

Desipramine has been used to facilitate withdrawal from chronic PCP use. The rationale is that PCP depletes norepinephrine concentrations in brain, and that this tricyclic antidepressant is the most selective blocker of norepinephrine uptake. Consequently, some of the deficiency of the neurotransmitter could be remedied. A dose of 25 to 50 mg was said to reduce craving for several hours. Six of eight patients treated with this drug were successfully withdrawn, while none of the eight offered other types of programs were successful (45). 

Belej T, Manji D, Sioutis S, Barros HM, Nobrega JN. (1996). Changes in serotonin and norepinephrine uptake sites after chronic cocaine pre- vs. post-withdrawai effects. Brain Res. 736(1-2) 287-96. Bennett TL. (1973). The effects of centraiiy biocking hippocampai theta activity on iearning and retention. Behav Biol. 9(5) 541-52. 

The mechanism of action of doxepin is presumable linked to the effect on the adrenergic transmission in the CNS, in particular to the blockage of neuronal norepinephrine uptake. Doxepin is used in anxious-depressive and anxious conditions, neuroses, alcoholism, organic illnesses of the CNS, and psychoses. The most frequently used synonyms are adapin and sinequan. 

Maprotiline and amoxapine are selective norepinephrine uptake inhibitors. They share most of the properties of the tricyclic antidepressants. Maprotiline has less sedating effect than mianserin and it is more epileptogenic than any other antidepressant. It shows considerable cardiotoxicity when taken in overdose. 

Richelson, E. and Pfenning, M. (1984) Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol 104 277-286. 

To date, however, no direct test of this possibility in humans has been conducted, presumably because of fears that the combination of acute CXj adrenoceptor and norepinephrine uptake blockage might produce unacceptable... 

As already noted, initiating treatment with the combination of an Oj antagonist with a norepinephrine uptake inhibitor (or serotonin uptake inhibitor... 

Cameron OG, Smith CB Comparison of acute and chronic lithium treatment on 3H-norepinephrine uptake by rat brain slices. Psychopharmacology 67 81-85, 1980... 

In contrast, clomipramine s major metabolite, desmethylclomipramine, has a markedly different pharmacological profile from the parent drug ( 35). While clomipramine is a potent inhibitor of serotonin uptake, desmethylclomipramine is a more potent inhibitor of norepinephrine uptake. If clomipramine s value in obsessive-compulsive disorder (OCD) depends on its ability to block 5-HT uptake (and not of norepinephrine), then this effect should be a function of the relative ratio between clomipramine and desmethylclomipramine. Thus, clomipramine could lose its effectiveness for OCD if a patient were an efficient demethylator of this drug. 

Codd, E. E., Shank, R. P., Schupsky, J. J., Raffa, R. B. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics structural determinants and role in antinociception, J. Pharmacol. Exp. Ther. 1995, 274, 1263-1270. 

To review adrenergic modulators such as dopamine and norepinephrine uptake inhibitors. 

Use of a BINAP/chiral diamine Ru complex trans- RuCl2[(R)-xylbinap][(R)-daipen] or the S,S complex efficiently catalyzes asymmetric hydrogenation of heteroaromatic ketones, with little influence of the ring properties on the enantioselectivity. Duloxetine, an inhibitor of serotonin and norepinephrine uptake carriers, has been synthesized in this way (Ohkuma, 2000b). 

Considerable attention has been paid to the ultimate postsynaptic effects of increased neurotransmitters in the synapses. In tests of postsynaptic effects, cAMP concentrations have consistently decreased rather than increased, in spite of the presumably longer duration of action of the transmitters. In addition, the number of postsynaptic -adrenoceptors has shown a measurable decrease that follows the same delayed time course as clinical improvement in patients. Thus, the initial increase in neurotransmitter seen with some antidepressants appears to produce, over time, a compensatory decrease in receptor activity, ie, down-regulation of receptors. Decreases in norepinephrine-stimulated cAMP and in B-adrenoceptor binding have been conclusively shown for selective norepinephrine uptake inhibitors, those with mixed action on norepinephrine and serotonin, monoamine oxidase inhibitors, and even electroconvulsive therapy. Such changes do not consistently occur after the selective serotonin uptake inhibitors, 2 receptor antagonists, and mixed serotonin antagonists. 

Maprotiline (a tetracyclic drug) is most like desipramine in terms of its potent norepinephrine uptake inhibition. Like the latter drug, it has fewer sedative and antimuscarinic actions than the older tricyclics. 

The serotonin reuptake inhibitors have been shown to be uniquely effective for treating these disorders. Recent studies have focused on fluoxetine and other selective serotonin reuptake-inhibiting drugs, although clomipramine, a mixed serotonin and norepinephrine uptake inhibitor, may be more potent. Fluvoxamine is marketed exclusively for this disorder in the United States. 

SSRIs show efficacy in social phobia, and combined serotonin and norepinephrine uptake inhibitors are effective in generalized anxiety disorder. 

Other suggested mechanisms include reduced excitatory neurotransmission by decreasing the release of glutamate, inhibition of norepinephrine uptake, reversible MAO-B inhibition, or dopamine antagonism. 

Bohm M., La Rosee, K., Schwinger, R.H., and Erdmann, E. 1995. Evidence for reduction of norepinephrine uptake sites in the failing human heart. J. Am. Coll. Cardiol. 25 146-153. 

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