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anemone toxins, do not discriminate between TTX-sensitive and TTX-insensitive channels. In fact the
scorpion toxins are less potent cardiac stimulants than the Type 1 anemone toxins [29]. Thus, while it
will be interesting to compare the sodium channel binding surfaces of the two classes of toxin as these
surfaces become better defined in each case, more useful input to the design of a positive inotrope acting
at site 3 is likely to come from direct studies on the anthopleurins.
VI. Defining the Cardioactive Pharmacophore
Now that high-resolution structures are available for both AP-A [46] and AP-B [47], we can begin to
interpret the results described above in terms of an emerging picture of the cardioactive pharmacophore
of these molecules. It is encouraging that most of the residues that have been shown hitherto to be
important for activity lie on one face of the structures, as shown in Figure 6. Of the residues highlighted
in Figure 6a, evidence to support their role in activity on the neuronal or cardiac channels (or both) has
come from chemical modification or site-directed mutagenesis studies except in the case of Asn35. The
reason for including this residue is that in AP-B it is close to the Asp7/Lys37/His39 region and its side
chain is hydrogen bonded to the backbone carbonyl of Lys37 [47]. Moreover, it is conserved throughout
the Type 1 toxins (Figure 2).
We anticipate that many of the residues highlighted in Figure 6 will participate in interactions with the
sodium channel binding site. One residue which may not is Asp9, the side-chain carboxylate of which
hydrogen bonds with the amide of Cys6 in AP-A and AP-B. Thus, it is possible that this residue has a
“structural” role rather than a “functional” one. Other residues in the vicinity of the pharmacophore that
may also have a structural role are Gly10 and Pro11, as discussed above. The side chain of Ser8 is
exposed and on the same surface of the molecule, placing it in a position potentially to interact with the
sodium channel; it is also conserved throughout the Type 1 toxins.
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