Norepinephrine reuptake antagonists

Norepinephrine reuptake antagonists (NETs) have antidepressant activity and have been found to be effective in the treatment of attention deficit hyperactivity disorder (ADHD). (/ )-tomoxetine (Strattera ) 95 is a marketed drug with a label indication for ADHD. Control of the absolute stereochemistry of these compounds is critical in that the (S) enantiomer is nine times less potent. The CBS reduction could be used to set the desired chirality as demonstrated in the reduction of 93 to produce alcohol 94.26 This intermediate could then be readily converted into 95. 

MAOI, monoamine oxidase inhibitor SARI, serotonin antagonist and reuptake inhibitor SNRI, serotonin and norepinephrine reuptake inhibitor SSRI, selective serotonin reuptake inhibitor TCA, tricyclic antidepressant. 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

FIGURE 6-43. Icon of paroxetine with muscarinic/cholinergic antagonist actions (mACH), norepinephrine reuptake inhibition (NRI), and serotonin 2D6 and 3A4 inhibition, in addition to serotonin reuptake inhibition (SRI). 

Nefazodone is the prototypical member of the SARI class of antidepressants. It is a powerful serotonin 2A antagonist with secondary actions as a serotonin and norepinephrine reuptake inhibitor (Figs. 7—14 and 7—15). Nefazodone also blocks alpha 1 receptors, but the clinical consequences of this are generally not important, perhaps because its norepinephrine reuptake inhibition reduces this action in vivo. 

FIGURE 6-27. Shown here is an icon of a tricyclic antidepressant (TCA). These drugs are actually five drugs in one (1) a serotonin reuptake inhibitor (SRI) (2) a norepinephrine reuptake inhibitor (NRI) (3) an anticholinergic/antimuscarinic drug (Ml) (4) an alpha adrenergic antagonist (alpha) and (5) an antihistamine (HI). 

Nefazodone [Serzone] Slight inhibition of serotonin and norepinephrine reuptake may also block CNS serotonin receptors Sedating useful in agitation May cause orthostatic hypotension because of antagonistic effect on vascular alpha-1 receptors... 

Amphetamine. Amphetamine facilitates dopamine release and inhibits norepinephrine reuptake, which results in increased postsynaptic norepinephrine levels. Amphetamine increases wakefulness and reduces REM sleep. These effects may be prevented by the preadministration of pimozide, a specific D, receptor antagonist, which inhibits presynaptic dopamine release. Propranolol, a p-adrenergic blocker, does not prevent the effect of amphet-... 

As of yet, the pharmacological actions of Serzone and Desyrel are not completely understood. Like SSRIs they inhibit serotonin uptake. There is also evidence that they antagonize 5-HT2 serotonin receptors. Because of these two functions, Serzone and Desyrel are often referred to as SARIs (serotonin antagonists/reuptake inhibitors). Serzone also inhibits norepinephrine reuptake while Desyrel slightly stimulates alpha-adrenergic receptors. These small differences in pharmacological action can cause widely varying side effects, which will be discussed later on. 

Dual acting norepinephrine reuptake inhibitors and 5-HT2A receptor antagonists I Synthesis and activity of novel 3-(phenylsulfonyl)-1H-indoles... 

Bupropion is an atypical antidepressant drug that is the only nonnicotine-based prescription medicine approved for smoking cessation by the FDA. Its mechanism of action is presumed to be mediated by its capacity to block neuronal reuptake of dopamine and/or norepinephrine (Fiore et al. 2000). Relative to other antidepressants, bupropion has a relatively high affinity for the dopamine transporter (Baldessarini 2001). There is also evidence that bupropion acts as a functional nicotine antagonist, suggesting another potential mechanism by which bupropion could reduce smoking rates (Slemmer et al. 2000). 

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