Noradrenaline Reuptake Inhibitors

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Selective inhibition of noradrenaline reuptake has been shown to be an attractive approach for the treatment of a number of diseases. For example, reboxetine 14 (Sect. 4.1.1) is used clinically for the treatment of depression and atomoxetine 13 (Sect. 4.2.1) is a new therapy for the treatment of ADHD (Fig. 30). Furthermore, NRIs are under investigation as potential therapies for chronic pain, urinary incontinence, fibromyalgia and a variety of other indications [64,65]. A number of reviews have been published that summarize discoveries of NRIs [66-69].

Morpholine Analogues 4.1.1

Reboxetine

(±)-Reboxetine 14 [RBX; racemic mixture of (S,S) and (R,R) enantiomers] (Fig. 30) is an orally active, selective NRI developed and launched by Pharmacia & Upjohn (now Pfizer) for the treatment of depression. Reboxetine was launched in Europe in 1997 and since that time a number of primary papers

13: atomoxetine

13: atomoxetine

Fig. 30 Structures of reboxetine, esreboxetine and atomoxetine

Table 14 Binding affinities of (±)-racemic, (+)-(S,S) and (-)-(R,R) reboxetine

Compound

NET

SERT

Selectivity of K¡

Ki (nM)

Ki (nM)

of SERT/NET

Reboxetine

1.1

129

124

(+)-(S,S)-Reboxetine

0.2

2900

14500

(-)-(R,.R)-Reboxetine

7.0

104

15

Table 15 Binding affinities of (±)-racemic

and (+)-(S,S)-reboxetine for additional receptor

systems [K¡ (nM)]

Compound

Histamine

Serotonin

Muscarinic

Adrenergic

Hi

5-HT2C

«1

Reboxetine

1400

1500

3900

10000

(+)-(S,S)-Reboxetine

> 30000

3000

3000

> 10 000

Other receptors and enzymes tested with K > 10000 nM include: dopamine reuptake (DRI), muscarinic (M1, M2, M3, M4, M5), adrenergic (a2, £1, £2), dopaminergic (D1, D2, D3, D4), serotinergic (5-HT1A, 5-HT2A, 5-HT3, 5-HT4, 5-HT6, 5-HT7), adenosine (A1, A2), benzodiazepine (peripheral and central), L-type calcium channels, histaminergic (H2), imidazoline (I2), melatonin (mt1), N-methyl-D-aspartate (glutamate and channel sites), neurokinin (NK1), nicotinic (a3, a4, a7), sigma, MAO-A, MAO-B, NOS, tyrosine hydroxylase and xanthine oxidase

Other receptors and enzymes tested with K > 10000 nM include: dopamine reuptake (DRI), muscarinic (M1, M2, M3, M4, M5), adrenergic (a2, £1, £2), dopaminergic (D1, D2, D3, D4), serotinergic (5-HT1A, 5-HT2A, 5-HT3, 5-HT4, 5-HT6, 5-HT7), adenosine (A1, A2), benzodiazepine (peripheral and central), L-type calcium channels, histaminergic (H2), imidazoline (I2), melatonin (mt1), N-methyl-D-aspartate (glutamate and channel sites), neurokinin (NK1), nicotinic (a3, a4, a7), sigma, MAO-A, MAO-B, NOS, tyrosine hydroxylase and xanthine oxidase and comprehensive reviews have been published describing reboxetine's pharmacology, clinical efficacy, pharmacokinetics, safety and toleration [70-76].

The (+) enantiomer of reboxetine is being developed by Pfizer as a potential oral treatment of neuropathic pain and fibromyalgia [77]. Esreboxetine [(+)-(S,S)-reboxetine; SS-RBX] 93 is more potent than reboxetine racemate with respect to inhibiting the uptake of NA and much weaker at inhibiting uptake of 5-HT; the combination of these two pharmacologies makes esreboxetine highly selective for NRI over SRI [76] (Table 14). In addition, esreboxetine also demonstrates good selectivity over a range of aminergic receptors and other targets [78] (Table 15).

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