Norepinephrine-uptake inhibition

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. 

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. 

Talopram 45 and citalopram 46 (Fig. 3.11) are closely related analogues, but talo-pram is a norepinephrine uptake blocker with a selectivity factor of about 550 against serotonin uptake inhibition, whereas citalopram is a serotonin uptake blocker, with a selectivity of 3400 against norepinephrine uptake inhibition. A similar selectivity difference is observed for the even more closely related analogues nisoxetine 47 (norepinephrine uptake selectivity ca. 180) and fluoxetine 48 (serotonin uptake selectivity 54) (Fig. 3.11) [42]. 

The SAR for norepinephrine uptake inhibition by amphetamine analogs is similar to that for inhibition of 5-HT reuptake. The protypical unsubstituted derivative, 2-phenethyl-amine, is a weak uptake inhibitor in isolated rat heart membranes (IDgo = 1.1 jM) (143). Introduction of a methyl group at the Cl position adjacent to the amino group results in a 10-fold increase in potency (i.e., dexamphetamine, (8), 1D = 0.18 pAO (143). Sibutra-mine, a tertiary amine, shows moderate NE uptake activity iK = 350 nAO, but its des-methyl and di-desmethyl metabolites, (JD-BTS 54 354 (44) and (R)-BTS 54 505 (46), exhibit potent activity values <20 nM) (see Table 15.10) (71). 

In a Free Wilson analysis of norepinephrine-uptake inhibiting phenethylamines (50), including achiral analogs, racemates, and pure enantiomers, but also diastereomeric mixtures, different group contributions were attributed to the R and S substituents (9 variables n = 30 r = 0.963 s = 0.276) [812]. 

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... 

There is no place anymore for the amphetamines in our therapeutic armamentarium. The only indications for the other stimulants, modaflnil and methylphenidate, are respectively narcolepsy and the attention deflcit disorders (ADHD) and hyperactivity syndromes in children. Their mechanisms of action include enhanced release of dopamine and norepinephrine, re-uptake inhibition of dopamine and norepinephrine and to some extend monoamine oxidase inhibition. 

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. 

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

Lahti, R. A. Maickel, R. P. 1971, The tricyclic antidepressants - inhibition of norepinephrine uptake as related to potentiation of norepinephrine and clinical efficacy, Biochemical Pharmacology, vol. 20, pp. 482-486. 

This herb is also known as St. Joan s wort, klamath weed, and goatweed. It has historically been used for many purposes, but most recently it is marketed as an antidepressant. In fact, it outsells all conventional antidepressants in Germany. The active constituent is hypericin that seems to act as a weak monoamine oxidase MAO inhibitor and a selective serotonin reuptake inhibitor (SSRI). Dopamine and norepinephrine uptakes are also mildly inhibited. St. John s wort is available in many forms, as a tablet, tea, tincture, and the raw dried herb. For best results, a tablet standardized to contain 0.3% hypericin should be taken Kira by Lichtwer Pharma is the most extensively studied. Randomized, placebo-controlled trials using 300 mg of St. John s Wort three times daily have found it to be superior to placebo in mild to moderate depression. Response rates are generally regarded as inferior to conventional antidepressants, including... 

The monoamine oxidase inhibitors are associated with a number of undesirable side effects including weight gain, postural hypotension, sexual dysfunction, and insomnia. The most serious side effect is the risk of tyramine-re-lated hypertensive crisis, often referred to as the "cheese effect," which can be fatal. To avoid this situation patients taking MAOIs must limit their tyramine intake, and the restrictive diet required to accomplish this leads to low patient compliance. A similar interaction occurs when switching patients from MAOI to SSRI therapy, and a minimum 2-week washout period before commencement of SSRI therapy is essential to allow MAO levels to return to normal. The therapeutic effects of the TCAs derive from their inhibition of serotonin and norepinephrine uptake, al-... 

Synephrine, the N-methylated analog of OA, completely blocked uptake at this concentration. The two imidazolines, naphazoline and XAMI, were somewhat effective as uptake blockers (20-30% inhibition), comparable to DCDM and DDCDM. The tricyclic antidepressant desipramine, a known amine uptake blocker in vertebrates, showed good potency in the cockroach system, as originally described by Evans (21). Finally, the N-chloroethyl benzylamine derivative, xylamine, has been described as a potent, specific and irreversible inhibitor of norepinephrine uptake in mammals (25). It was an active inhibitor of uptake in the cockroach preparation. 

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