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domains contribute to formation of the transmembrane pore, which is believed to be lined by short
segments from the loops linking S5 and S6 in each domain. Binding site 3 is located on the extracellular
surface of the channel and involves regions of the loops between S5 and S6 in domains I and IV [37,45].
The binding sites for several modulators of sodium-channel activity, including the blocker tetrodotoxin,
have been mapped quite precisely onto the sequence (and thus the structural model of the channel) by
combining information derived from comparisons of naturally occurring variants of the channel and
from site-directed mutagenesis [37]. A similar approach could be applied to the definition of site 3, but
in the absence of a crystal structure for the α-subunit the three- dimensional structure of this site will
remain speculative. Therefore current attempts to design a low molecular mass analogue of the
anthopleurins must be based on the structure of the ligand rather than the receptor.
C. Development of a New Positive Inotrope
Being polypeptides, the anthopleurins have limited therapeutic potential in their own right, as they are
not active following oral administration and are antigenic in experimental animals [18]. Recent advances
in the field of peptide mimetics, however, lend credence to the concept of harnessing the favorable
cardiotonic properties of the anthopleurins in a low molecular mass, nonpeptide, synthetic compound.
The goal of such a development would be to retain the activity of the parent polypeptides in a molecule
that had good bioavailability and was not antigenic. Ideally, it might also be possible to increase the
cardiac selectivity of such a compound.
In order to achieve this goal, a knowledge of the three-dimensional structures of the anthopleurins and
their structure-function relationships is essential. Significant progress has been made towards these goals
over the past few years and we are now in a position to commence analogue design and synthesis. The
following sections in this chapter summarize our knowledge of the cardioactive pharmacophore of the
anthopleurins and the prospects for mimicking this in a nonpeptide moiety. Aspects of the
pharmacological profile which such a compound would need to display in order to be useful in CHF
therapy are also discussed.
III. 3D Structure
The structures in aqueous solution of both AP-A [46] and AP-B [47] have been solved using highresolution
1H NMR data. Structures have also been determined for the Type 1 toxin ATX Ia [48] and the
Type 2 toxin Sh I [49,50] from NMR data. The main secondary structure element in each of these
structures is a
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