Antitarget Explained

In pharmacology, an antitarget (or off-target) is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to ensure that new drugs do not show significant activity at any of a range of antitargets, most of which are discovered largely by chance.[1] [2]

Among the best-known and most significant antitargets are the hERG channel and the 5-HT2B receptor, both of which cause long-term problems with heart function that can prove fatal (long QT syndrome and cardiac fibrosis, respectively), in a small but unpredictable proportion of users. Both of these targets were discovered as a result of high levels of distinctive side-effects during the marketing of certain medicines, and, while some older drugs with significant hERG activity are still used with caution, most drugs that have been found to be strong 5-HT2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these targets.[3] [4] [5] [6] [7] [8]

Agonism of the 5-HT2A receptor is an antitarget because 5-HT2A receptor agonists are associated with hallucinogenic effects.[9] According to David E. Nichols, "Discussions over the years with many colleagues working in the pharmaceutical industry have informed me that if upon screening a potential new drug is found to have serotonin 5-HT2A agonist activity, it nearly always signals the end to any further development of that molecule." There are some exceptions however, for instance efavirenz and lorcaserin, which can activate the 5-HT2A receptor and cause psychedelic effects at high doses.[10] [11] [12]

The growth of the field of chemoproteomics has offered a variety of strategies to identify off-targets on a proteome wide scale.[13]

See also

Notes and References

  1. Klabunde . T.. Evers . A.. GPCR antitarget modeling: pharmacophore models for biogenic amine binding GPCRs to avoid GPCR-mediated side effects. ChemBioChem. 6. 5. 876–889. 2005. 15791686. 10.1002/cbic.200400369. 33198528.
  2. Price . D.. Blagg . J.. Jones . L.. Greene . N.. Wager . T.. Physicochemical drug properties associated with in vivo toxicological outcomes: a review. Expert Opinion on Drug Metabolism & Toxicology. 5. 8. 921–931. 2009. 19519283. 10.1517/17425250903042318. 34208589.
  3. 11994029. 2002. De Ponti . F.. Poluzzi. Cavalli. Recanatini. Montanaro. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. 25. 4. 263–286. Drug Safety . E. . A. . M. . N. . 10.2165/00002018-200225040-00004. 37288519.
  4. Recanatini . M.. Poluzzi . E.. Masetti . M.. Cavalli . A.. De Ponti . F.. QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Medicinal Research Reviews. 25. 2. 133–166. 2005. 15389727. 10.1002/med.20019. 34637861. free.
  5. Raschi . E.. Vasina . V.. Poluzzi . E.. De Ponti . F.. The hERG K+ channel: target and antitarget strategies in drug development. Pharmacological Research. 57. 3. 181–195. 2008. 18329284. 10.1016/j.phrs.2008.01.009.
  6. Raschi . E.. Ceccarini . L.. De Ponti . F.. Recanatini . M.. hERG-related drug toxicity and models for predicting hERG liability and QT prolongation. Expert Opinion on Drug Metabolism & Toxicology. 5. 9. 1005–1021. 2009. 19572824. 10.1517/17425250903055070. 207490564.
  7. Huang . X.. Setola . V.. Yadav . P.. Allen . J.. Rogan . S.. Hanson . B.. Revankar . C.. Robers . M.. Doucette . C.. Roth . B. L.. Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment. 76. 710–722. 2009. 19570945. 10.1124/mol.109.058057. 4. Molecular Pharmacology. 2769050.
  8. Bhattacharyya . S.. Schapira. Mikhailidis. Davar. Drug-induced fibrotic valvular heart disease. The Lancet. 374. 9689. 577–85. 2009 . 10.1016/S0140-6736(09)60252-X . A. H. . D. P. . J. . 19683643. 205953943.
  9. Nichols DE . Psychedelics . Pharmacol. Rev. . 68 . 2 . 264–355 . 2016 . 26841800 . 4813425 . 10.1124/pr.115.011478 .
  10. Treisman GJ, Soudry O . Neuropsychiatric Effects of HIV Antiviral Medications . Drug Saf . 39 . 10 . 945–57 . 2016 . 27534750 . 10.1007/s40264-016-0440-y . 6809436 .
  11. Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA . The HIV antiretroviral drug efavirenz has LSD-like properties . Neuropsychopharmacology . 38 . 12 . 2373–84 . 2013 . 23702798 . 3799056 . 10.1038/npp.2013.135 .
  12. Web site: Schedules of Controlled Substances: Placement of Lorcaserin into Schedule IV. 2013-05-08.
  13. Moellering. Raymond E.. Cravatt. Benjamin F.. January 2012. How Chemoproteomics Can Enable Drug Discovery and Development. Chemistry & Biology. 19. 1. 11–22. 10.1016/j.chembiol.2012.01.001 . 3312051. 1074-5521.

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