Synthesis and immunological effects of C14-linked 4,5-epoxymorphinan analogues as novel heroin vaccine haptens

Gutman, Eugene S.; Irvin, Thomas C.; Morgan, Jeffrey Brian; Barrientos, Rodell C.; Torres, Òscar; Beck, Zoltán; Matyas, Gary R.; Jacobson, Arthur E.; Rice, Kenner C.

doi:10.1039/d1cb00029b

Cited by 6 publications

(4 citation statements)

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“…We noted in the introduction the clinical importance of substitution therapy for drugdependent individuals with µOR partial agonists such as methadone or buprenorphine, sometimes in conjunction with naloxone. Vaccination and immunization present a promising alternate approach for treating substance dependence [212]. Here, an immunogenic carrier molecule (lipid, polysacharide, or protein such as tetanus toxoid (TT)) is conjugated to the surrogate of the target drug, the so-called hapten, which refers to a substance that can combine with a specific antibody but lacks intrinsic antigenicity.…”

Section: Azadienophilesmentioning

confidence: 99%

“…Haptens possess structural unit and functional groups (e.g., NH 2 , COOH, and SH) that facilitate their conjugation to an immunogenic carrier. Recently, Gutman et al [212] reported the synthesis of C14-linked 4,5-epoxymorphinan-type analogues (Figure 69) as putative heroin vaccine haptens. To this end, the novel heroin haptens, 6,14-AmidoHap (251), 14-AmidoMorHap ( 255), and 14-AmidoHerHap (256) were synthesized from thebaine (4).…”

Section: Azadienophilesmentioning

confidence: 99%

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Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

et al. 2022

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6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.

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Section: Azadienophilesmentioning

confidence: 99%

Section: Azadienophilesmentioning

confidence: 99%

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

et al. 2022

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“…In this final formulation, the active immunogen is the protein–hapten conjugate. The design and efficacy of vaccines to drugs of abuse—for heroin [ 8 , 9 , 10 ], fentanyl [ 11 , 12 ], oxycodone [ 13 ], methamphetamine [ 14 ], morphine [ 15 ], and others [ 5 ]—have been reported and extensively studied in animals. It is known that hapten design impacts the specificity of the vaccine-induced antibodies [ 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…In our continuing effort to develop effective anti-heroin vaccines [ 10 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], we have now designed a series of haptens ( 1 – 4 , Figure 1 b) 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 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines

Sulima

Morgan

et al. 2022

Molecules

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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.

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