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.{{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hERG activity are still used with caution, most drugs that have been found to be strong 5-HT2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these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.{{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 }} 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.{{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 }}{{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 }}{{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}}
The growth of the field of chemoproteomics has offered a variety of strategies to identify off-targets on a proteome wide scale.{{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 | pmc=3312051|issn=1074-5521}}