Antitarget

{{Short description|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.<ref>{{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 }}</ref><ref>{{Cite journal | 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 }}</ref>

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hERG activity are still used with caution, most drugs that have been found to be strong 5-HT2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these targets.<ref>{{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 }}</ref><ref>{{Cite journal | 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 }}</ref><ref>{{Cite journal | 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 }}</ref><ref>{{Cite journal | 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 }}</ref><ref>{{Cite journal | 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 }}</ref><ref>{{Cite journal | 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 }}</ref>

Agonism of the 5-HT2A receptor is an antitarget because 5-HT2A receptor agonists are associated with hallucinogenic effects.<ref name="pmid26841800">{{cite journal | vauthors = Nichols DE | title = Psychedelics | journal = Pharmacol. Rev. | volume = 68 | issue = 2 | pages = 264–355 | year = 2016 | pmid = 26841800 | pmc = 4813425 | doi = 10.1124/pr.115.011478 }}</ref> 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."<ref name="pmid26841800" /> There are some exceptions however, for instance efavirenz and lorcaserin, which can activate the 5-HT2A receptor and cause psychedelic effects at high doses.<ref name="pmid27534750">{{cite journal | vauthors = Treisman GJ, Soudry O | title = Neuropsychiatric Effects of HIV Antiviral Medications | journal = Drug Saf | volume = 39 | issue = 10 | pages = 945–57 | year = 2016 | pmid = 27534750 | doi = 10.1007/s40264-016-0440-y | s2cid = 6809436 }}</ref><ref name="pmid23702798">{{cite journal | vauthors = Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA | title = The HIV antiretroviral drug efavirenz has LSD-like properties | journal = Neuropsychopharmacology | volume = 38 | issue = 12 | pages = 2373–84 | year = 2013 | pmid = 23702798 | pmc = 3799056 | doi = 10.1038/npp.2013.135 }}</ref><ref name="FederalRegister2013">{{cite web | url=https://www.federalregister.gov/documents/2013/05/08/2013-10895/schedules-of-controlled-substances-placement-of-lorcaserin-into-schedule-iv | title=Schedules of Controlled Substances: Placement of Lorcaserin into Schedule IV| date=2013-05-08}}</ref>

The growth of the field of chemoproteomics has offered a variety of strategies to identify off-targets on a proteome wide scale.<ref>{{Cite journal|last1=Moellering|first1=Raymond E.|last2=Cravatt|first2=Benjamin F.|date=January 2012|title=How Chemoproteomics Can Enable Drug Discovery and Development|url=|journal=Chemistry & Biology|volume=19|issue=1|pages=11–22|doi=10.1016/j.chembiol.2012.01.001 |pmid=22284350 | pmc=3312051|issn=1074-5521}}</ref>

==See also== *Off-target activity

==References== {{Reflist|2}}

Category:Medicinal chemistry Category:Drug discovery