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whereas, calcium sensitizers such as EMD 57033 may be useful positive inotropic compounds, even in
the diseased myocardium [12].
Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel
modulators increase Na + influx and prolong the plateau phase of the action potential; sodium/calcium
exchange then leads to an increase in the level of calcium available to the contractile elements, thus
increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF
9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation
[15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing
human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and
potassium channel activities also function as positive inotropes [13], but in the remainder of this article
we shall focus on sodium channel modulators.
II. The Anthopleurins
Two decades ago “drugs from the sea” were the subject of high expectations and a good deal of effort in
various centers around the world. The number of therapeutically useful compounds to have emerged
from that effort has been rather limited, but with the advent of high-throughput screening it is likely that
useful new leads will be found, even from species investigated previously. Notwithstanding, some
valuable leads did emerge from work carried out in the 1970s, amongst which were the polypeptide
cardiac stimulants known as the anthopleurins. These were isolated from sea anemones, where they are
components of the animal's venom and are believed to have a function in defense and the capture of
prey. The work that led to the isolation and characterization of these and related polypeptides from sea
anemones is covered in earlier reviews [18,19] and will not be reiterated here.
The best characterized of the anthopleurins is anthopleurin-A (AP-A), which was isolated from the
northern Pacific sea anemone Anthopleura xan- thogrammica and consists of 49 residues cross-linked
by three disulfide bonds [18,20]. It is active as a cardiac stimulant at nanomolar concentrations in vitro,
making it some 200 fold more potent on a molar basis that digoxin. Its positive inotropic activity is not
associated with any significant effects on heart rate or blood pressure [21], and in conscious dogs its
therapeutic index is 7.5, which is about three-fold higher than that of digoxin [8]. Anthopleurin-A is
active under conditions of stress and hypocalcaemia [18,22], as well as in ischemic myocardium where
many other positive inotropes give equivocal results [23]. The profile of activity for AP-A suggests that
it is a potentially valuable lead in the development of an alternative positive inotrope to digoxin
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