Biomedical Engineering Reference
In-Depth Information
18.3.1.2.2 Other Selective Serotonin Reuptake Inhibitors
In Figure 18.6, the seven SSRIs that have reached the market, with the priority dates of the i rst
patent application indicated are shown. However, the two i rst compounds on the market were both
withdrawn due to serious, although rare, side effects. Zimelidine (
18.47
) was found to induce an
inl uenza-like symptom in 1%-2% of the patients, which in rare cases (1/10,000) resulted in the
so-called Guillain-Barré syndrome. The drug was withdrawn in 1983 after 1½ years on the market.
Indalpine (
18.48
) induced agranulocytosis in one of 20,000 patients and was withdrawn in 1984.
As it appears from Figure 18.6, all the marketed SSRIs (except sertraline) were discovered in
the i rst half of the 1970s, meaning that the companies lacked sufi cient information regarding the
structural classes their competitors were developing. Accordingly, rather diverse structures were
developed. However, they were all selective 5-HT reuptake inhibitors (Table 18.3), although their
selectivity ratios vary signii cantly, citalopram/escitalopram being the most selective compounds. In
general, the SSRIs have low afi nity for receptors for DA, NE, 5-HT, and other neurotransmitters,
although exceptions exist. With regard to interaction with cytochrome P450 enzymes there are vital
differences, e.g., paroxetine and l uoxetine having signii cant afi nity for CYP2D6.
TABLE 18.3
The Effect of SSRIs, Talopram, and Talsupram on the Inhibition
of Reuptake of 5-HT, NE, and DA
Uptake Inhibition IC
50
(nM)
Ratio
Compound
5-HT
NE
DA
NE/5-HT
DA/5-HT
Citalopram (
18.43
)
3.9
6100
40,000
1560
10,300
Escitalopram (
S
) (
18.43
)
2.1
2500
65,000
1200
31,000
R
-citalopram (
R
) (
18.43
)
275
6900
54,000
25
200
Indalpine (
18.48
)
2.1
2100
1,200
1000
570
Sertraline (
18.49
)
0.19
160
48
840
250
Paroxetine (
18.45
)
0.29
81
5,100
280
17,600
Fluvoxamine (
18.46
)
3.8
620
42,000
160
11,000
Zimeldine (
18.47
)
56
3100
26,000
55
460
Fluoxetine (
18.44
)
6.8
370
5,000
54
740
0.00006
a
Talopram (
18.32
)
1400
2.5
44,000
0.0017
0.00008
a
Talsupram (
18.33
)
770
0.79
9,300
0.0010
Sources:
Data in italics are from Hyttel, J.
Int. Clin. Psychopharmacol
. 9(Suppl. 1), 19, 1994;
Remaining are from Lundbeck Screening Database, H. Lundbeck A/S, Valby,
Denmark.
a
NE/DA.
18.3.1.3 Discovery of Escitalopram—An Allosteric Serotonin Reuptake Inhibitor
The 5-HT reuptake inhibition of citalopram resides in the (
S
)-enantiomer (escitalopram) whereas the
(
R
)-enantiomer is about 100 times less potent. Escitalopram was launched as a single-enantiomer
drug in 2002 and is today an effective antidepressant with several advantages as compared to citalo-
pram and other SSRIs. In preclinical studies escitalopram shows greater efi cacy and faster onset of
action than comparable doses of citalopram. This is attributed to the fact that a number of studies
have shown that the (
R
)-enantiomer of citalopram counteracts the activity of the (
S
)-enantiomer.
Further in randomized, controlled clinical studies escitalopram shows better efi cacy than citalopram,
with higher response and remission rates, and faster onset of action.
