Drugs as Inhibitors of Monoamine Transporters

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The most important CNS drugs that target the norepinephrine and serotonin neurotransmitter transporters (NET and SERT) are the tricyclic antidepressants and their modern counterparts. The discovery that imipramine potently inhibited NET in sympathetic nerves [10] and the finding that this also applied in the brain [11] led to the first understanding of the mechanism of action of the tricyclic antidepressants. Following the discovery of the serotonin uptake system in brain it soon became apparent that the classical tricyclic drugs imipramine and amitriptyline were also potent inhibitors of SERT. This reinforced the "monoamine hypothesis of depression" as a monoamine deficiency state, and stimulated much further research in the pharmaceutical industry to discover new inhibitors of monoamine uptake. An effort to improve the selectivity of antidepressants was made in the 1970's by scientists at the CIBA-GEIGY Company in Switzerland (now Novartis), who developed the selective norepinephrine uptake inhibitor maprotiline [12]. This proved to be clinically effective as an antidepressant but it was not a great success commercially and had few clear advantages over the classical TCAs. The serotonin selective reuptake inhibitors (SSRIs) developed in the 1990's proved to be far more important. The first SSRI zimelidine was launched by Astra in Europe in the 1980's, but it had to be withdrawn because of serious adverse side effects [13]. The first widely used SSRI was fluoxetine ("Prozac") [14]. It was followed by a number of other SSRI's, several of which met with considerable commercial success. Although the SSRI's were no more efficacious than the first generation tricyclic antidepressants, and did not act any faster, they were considerably safer in over-dose and were used more widely. The first generation of tricyclic antidepressants were very effective in the treatment of major depression but suffered from a number of adverse side effects caused by secondary actions on a variety of monoamine receptors and conduction mechanisms in the heart. The latter effects could prove lethal if the drugs were used in too high a dose - and many depressed patients committed suicide in this way in the 1960' & 70's. The greatly improved safety profile of the SSRI's allowed an expansion of the approved indications for the use of these drugs to include a variety of other psychiatric indications (Table 1). Apart from the use of these drugs in various phobic conditions, a major change in recent years has been the recognition of their effectiveness in the treatment of generalized anxiety disorder, and the first FDA approval of antidepressant compounds for this indication (venlafaxine, duloxetine, and escitalopram ). In addition, agents in this class in controlled trials have shown usefulness in treating pre-menstrual dysphoria, borderline personality disorder, obesity, smoking cessation, and alcoholism.

Table 1. FDA-Approved Indications for SSRI and mixed NE/5-HT Antidepressants in addition to major depression

Bulimia nervosa Panic disorder

Obsessive compulsive disorder (OCD) Generalized anxiety disorder Social anxiety disorder Post-traumatic stress syndrome

Table 2. Antidepressants: Inhibition of Human Serotonin (SERT), Norepinephrine (NET), and Dopamine (DAT) Transporters

Generic Name

Human SERT,

Human NET,

Human DAT,

Selectivity:

Kd (nM)

Kd (nM)

Kd (nM)

SERT vs NET

Amitriptyline

4.3

35

3250

8

Amoxepine

58

16

4310

0.3

Bupropion

9100

52,000

520

5.7

Citalopram

1.2

4070

28,100

3500

Clomipramine

0.3

38

2190

130

Desipramine

17.6

0.8

3190

0.05

Dothiepin

8.6

46

5310

5.3

Doxepine

68

29.5

12,100

0.4

Duloxetine

0.8

7.5

240

9.4

Escitalopram

2.5

2514

>100,000

>1000

Fluoxetine

0.8

240

3600

300

Fluvoxamine

2.2

1300

9200

580

Imipramine

1.4

37

8500

27

Lofepramine

70

5.4

18,000

0.08

Maprotiline

5800

11.1

1000

0.002

Mirtazapine

>100,000

4600

>100,000

Nefazodone

200

360

360

1.8

Nortriptyline

18

4.4

1140

0.24

Paroxetine

0.13

40

490

300

Protriptyline

19.6

1.4

2100

0.07

Reboxetine

129

1.1

0.008

Sertraline

0.29

420

25

1400

Trazodone

160

8500

7400

53

Trimipramine

149

2450

780

16

Venlafaxine

8.9

1060

9300

120

(From Glennon and Iversen, [20])

(From Glennon and Iversen, [20])

Some of the most recently introduced antidepressants hark back to the less-selective compounds of the earlier era. Thus duloxetine [15] and venlafaxine [16] are drugs that combine both norepinephrine and serotonin re-uptake inhibition although in vitro binding data show that venlafaxine binds with more than 100 times higher affinity to human SERT than to NET, (Table 2). Reboxetine is the first antidepressant drug since maprotiline in a new class of NET-selective inhibitors [17,18]. Reboxetine is reported to be as effective as the SSRI's or older tricylics, but is not associated with sexual dysfunction, a common side effect of the SSRI's. It is claimed to be more effective than fluoxetine in improving the social adjustment of depressed patients. The SSRI's and the more recently developed mixed NET/SERT antidepressants have proved hugely successful commercially, with worldwide sales well in excess of $10 billion. Table 2 summarizes the affinities of currently used antidepressants on cloned human monoamine transporters expressed in tissue culture cell lines [19].

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