Antitarget

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Concept in pharmacology

title: "Antitarget" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["medicinal-chemistry", "drug-discovery"] description: "Concept in pharmacology" topic_path: "science/chemistry" source: "https://en.wikipedia.org/wiki/Antitarget" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Concept in pharmacology ::

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.{{Cite journal | last1 = Klabunde | first1 = T. | last2 = Evers | first2 = A. | title = GPCR antitarget modeling: pharmacophore models for biogenic amine binding GPCRs to avoid GPCR-mediated side effects | journal = ChemBioChem | volume = 6 | issue = 5 | pages = 876–889 | year = 2005 | pmid = 15791686 | doi = 10.1002/cbic.200400369 | s2cid = 33198528 | last1 = Price | first1 = D. | last2 = Blagg | first2 = J. | last3 = Jones | first3 = L. | last4 = Greene | first4 = N. | last5 = Wager | first5 = T. | title = Physicochemical drug properties associated with in vivo toxicological outcomes: a review | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 5 | issue = 8 | pages = 921–931 | year = 2009 | pmid = 19519283 | doi = 10.1517/17425250903042318 | s2cid = 34208589

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hERG activity are still used with caution, most drugs that have been found to be strong 5-HT2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these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.{{Cite journal | pmid = 11994029 | year = 2002 | last1 = De Ponti | first1 = F. | last2 = Poluzzi | last3 = Cavalli | last4 = Recanatini | last5 = Montanaro | title = Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview | volume = 25 | issue = 4 | pages = 263–286 | journal = Drug Safety | first2 = E. | first3 = A. | first4 = M. | first5 = N. | doi=10.2165/00002018-200225040-00004 | s2cid = 37288519 | last1 = Recanatini | first1 = M. | last2 = Poluzzi | first2 = E. | last3 = Masetti | first3 = M. | last4 = Cavalli | first4 = A. | last5 = De Ponti | first5 = F. | title = QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development | journal = Medicinal Research Reviews | volume = 25 | issue = 2 | pages = 133–166 | year = 2005 | pmid = 15389727 | doi = 10.1002/med.20019 | s2cid = 34637861 | doi-access = free | last1 = Raschi | first1 = E. | last2 = Vasina | first2 = V. | last3 = Poluzzi | first3 = E. | last4 = De Ponti | first4 = F. | title = The hERG K+ channel: target and antitarget strategies in drug development | journal = Pharmacological Research | volume = 57 | issue = 3 | pages = 181–195 | year = 2008 | pmid = 18329284 | doi = 10.1016/j.phrs.2008.01.009 | last1 = Raschi | first1 = E. | last2 = Ceccarini | first2 = L. | last3 = De Ponti | first3 = F. | last4 = Recanatini | first4 = M. | title = hERG-related drug toxicity and models for predicting hERG liability and QT prolongation | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 5 | issue = 9 | pages = 1005–1021 | year = 2009 | pmid = 19572824 | doi = 10.1517/17425250903055070 | s2cid = 207490564 | last1 = Huang | first1 = X. | last2 = Setola | first2 = V. | last3 = Yadav | first3 = P. | last4 = Allen | first4 = J. | last5 = Rogan | first5 = S. | last6 = Hanson | first6 = B. | last7 = Revankar | first7 = C. | last8 = Robers | first8 = M. | last9 = Doucette | first9 = C. | last10 = Roth | first10 = B. L. | title = Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment | volume = 76 | pages = 710–722 | year = 2009 | pmid = 19570945 | doi = 10.1124/mol.109.058057 | issue = 4 | journal = Molecular Pharmacology | pmc = 2769050 | last1 = Bhattacharyya | first1 = S. | last2 = Schapira | last3 = Mikhailidis | last4 = Davar | title = Drug-induced fibrotic valvular heart disease | journal = The Lancet | volume = 374 | issue = 9689 | pages = 577–85 | year = 2009 | doi = 10.1016/S0140-6736(09)60252-X | first2 = A. H. | first3 = D. P. | first4 = J. | pmid=19683643 | s2cid = 205953943

Agonism of the 5-HT2A receptor is an antitarget because 5-HT2A receptor agonists are associated with hallucinogenic effects. 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.

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

References

References

  1. (2016). "Psychedelics". Pharmacol. Rev..
  2. (2016). "Neuropsychiatric Effects of HIV Antiviral Medications". Drug Saf.
  3. (2013). "The HIV antiretroviral drug efavirenz has LSD-like properties". Neuropsychopharmacology.
  4. (2013-05-08). "Schedules of Controlled Substances: Placement of Lorcaserin into Schedule IV".
  5. (January 2012). "How Chemoproteomics Can Enable Drug Discovery and Development". Chemistry & Biology.

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