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MOLECULAR SCREENING OF PROSPECTIVE CANDIDATES FOR TRPA1 ION CHANNEL SELECTIVE ANTAGONISTS

TRPA1 is an ankyrin receptor of TRP family. It is mostly expressed in the smalldiameter nociceptors with cell bodies located in the dorsal roots, as well as in trigeminal, nodose and jugular ganglia. Recently, more and more information has been found in the literature on the role of TRPA1 in the realization of cold and pain sensitivity, and also in the formation and maintenance of inflammation. Subject to these data there is an increasing interest in finding and studying pharmacological agents able to selectively block the TRPA1 receptors and thereby reduce the severity of pain and inflammation. Using the molecular modeling techniques, we analyzed spectra of biological activity of a series of promising candidates for selective antagonists of TRPA1 ion channel in order to find potentially active compounds against pain and inflammation. Substances that showed in high throughput screening the percentage of the cellular calcium response inhibition above 50% - 3*SD maximum and its own agonistic activity less than 10% + 3*SD minimum were identified as hits. The value IC50 for hits was determined immediately after re-testing at 10 μM concentration and repeatedly after the determination of the leading chemical series. As the result of the studies, the biologically active molecules of leading chemical series have been confirmed. The research was partially supported by the grant of the President of the Russian Federation №MD-4711.2015.7 and МК-6135.2016.4.

Иллюстрации

 

Table 1.  Summary table with IC50 data for verifiable hits

Figure 1. The concentration dependence of antagonist activity on the concentration for verifiable hits and control antagonist RR. Each concentration point is the average of two repetitions. Partial antagonists.

Figure 2. The concentration dependence of antagonist activity on the concentration for verifiable hits and control antagonist RR. Each concentration point is the average of two repetitions. Full antagonists.

Figure 3. The concentration dependence of antagonist activity on the concentration for verifiable hits and control antagonist RR. Each concentration point is the average of two repetitions. Full antagonists.

DOI: 10.18413/2313-8971-2016-2-1-63-66
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