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Document Page 300 polypeptides BDS I and II [40,41], which were claimed to have antihypertensive and antiviral activity, and the α-scorpion toxins [24,27,42]. As discussed below, we may expect to obtain some useful information from comparisons of the molecular surfaces of these different classes of polypeptides, but the utility of this approach depends on the extent to which their binding sites are identical and not just partially overlapping, as well as the issue of channel sub-type specificity of the different toxins. The synthetic agent DPI 201-106 has been evaluated extensively as a potential replacement for digoxin [43]. It is a potent positive inotrope that also acts by delaying inactivation of the sodium channel, but its binding site appears to be distinct from that of ATX II [44]. Moreover, it exerts antihypertensive and local anesthetic effects and may also antagonise the calcium channel [43]. At present we are not aware of any low molecular mass compound that binds to the same site as the anthopleurins. This offers the prospect that a mimetic based on the anthopleurins might have a pharmacological profile distinct from other positive inotropes. The structure of the receptor for the anthopleurins, the α-subunit of the voltage-gated sodium channel, is known only in schematic form [35–37]. As illustrated in Figure 3, it contains four homologous domains, each consisting of six transmembrane regions (assumed to be helices) designated S1 to S6. The S4 segments are thought to act as the voltage sensors of the channel. All four Figure 3 Schematic of the α-subunit of the voltage-gated sodium channel, based on its amino acid sequence [35–37]. The transmembrane segments S1–S6 in each domain are thought to form helices—with the positively charged S4 segment acting as a voltage sensor—and the S5–S6 loop of each domain is thought to contribute to the transmem-brane pore. Site 3 includes regions of the S5–S6 loops of domains I and IV, and the inactivation gate (h) is located on the intracellular segment linking domains III and IV. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_300.html (1 of 2) [4/5/2004 5:20:56 PM]
Document Page 301 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_301.html [4/5/2004 5:21:01 PM]
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