Abstract
In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)–hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT–hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT–hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness.
Highlights
130,000 Americans died from drug overdose due to heroin from 1999 to 2019, an average of more than four deaths for every 100,000 people [1]
We have reported that a hapten for an effective heroin vaccine was highly dependent on the specific substituent at the C6 position [19]; former work indicated that a C6-amido substituent was the most useful substituent of the several that we designed for a heroin vaccine [19]
While all tetanus toxoid (TT)–hapten conjugates induced high antibody endpoint titers to the targets, only TT-2 and TT-3 showed protection against heroin, suggesting that antibody titers may not predict the efficacy of heroin vaccines in vivo
Summary
130,000 Americans died from drug overdose due to heroin from 1999 to 2019, an average of more than four deaths for every 100,000 people [1]. There are three main components of vaccines against small-molecule drugs: (1) a molecular surrogate of the target drug called a hapten, (2) an immunogenic protein, and (3) an adjuvant. Vaccine-induced antibodies should not cross-react with existing drugs used to treat OUD [5] To this end, it is extremely important to determine the optimum hapten design that would induce antibodies with the desired specificity. In our continuing effort to develop effective anti-heroin vaccines [10,16,18–25], we have designed a series of haptens (1–4, Figure 1b) based on the attachment of the linker to the C1 position in the 4,5-epoxymorophinan nucleus. Haptens have previously been examined with a linker attached to the nitrogen atom, as well as at the C3, C6, and C14 positions of the 4,5-epoxymorphinan nucleus [17–19] Our studies of those compounds led to the proposal of a facial recognition hypothesis [16]. WWiitthh 66 iinnhhaanndd,,wweessoouugghhtttotoinintrtorodduuceceananamaminionogrgoruopuaptatht ethCe1Cp1opsiotisoitniovniavniaitrnaittiroantoionnanoWnaciattnhivaa6ctteiindvahCtae1dn, fdCo,l1lw,ofweolesldoowubgeydhrtebdtyourcietndioturnoctodiofuntcheoefantnihteraomngitirrnooougpgr.orMouupap.nMyatanntithyreantCiiotr1natpciooonnsidctiiotoniondnivs-ia nitratwioennresowanteteraemnapatttceetmdiv.paNtteeedidt.hNCeer1in,thiftoerrollnnoiiwturmoendtiuebtmyrartfleeutdroaurfoclubtiooorrnoabtoeofirnathtDeeMinnSiDtOrMoaStgOrrooaoutmpro.toeMmmaptneemyrapntueitrrraeatuntirooern conditnsiooodrnissuomwdienurimetraanttietterimanteapcitenetdiac.caeNctiiecditaghcaiedvregnaaintvryeonanniituyramntiiottrneat,trwiaofhnli,ulewosrhooidlbeiousromadtnieuiitmnritDneiMitnriStTeOFiAnatdTreFocAoommdepctooesmed-perature npthooesressduobtdshtieruasmtueb6ns.ittrAraatcetlea6s.isnAicaclclaeHstNiscicOaa3cl/iHdHN2gSOaOv3/4eHian2SnnOyit4rnionimtrneaittthriooamnne,ewaththa−nil2ee0as◦toC−d2gi0uav°mCe angamitvrieixttaeurmienioxTftFuthAree decompodfoetshierededdtehpseriroesdduubpcstrto7rd,aputehcte6n7.,oApl h8c,elannsosldi8co,avalenHrd-nNoivtOrea3rt/-eHndi2tSpraOrtoe4ddiunpcrtno9idt,ruloickmte9ley,tlhtihkaeenlreyeasthutel−tr2oe0fsun°Clittrogaftainvoinetraoa-fmixture otpifohnethnoeofldp8heasefintreoerldl8opassrftooedrf utlhocsetsh7oy,fdptrhhoeelynhtoyicdlar8lol,ylayuntindcsatloalyvbleuern-anscteiattbraalteetea(dScecphtaertomed(eSu2cc)ht.e9m, eli2k)e.ly the result of nitration of phenol 8 after loss of the hydrolytically unstableNaOce2tate (Scheme 2)
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