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The synthesis of α-methyl amino acid building blocks and their incorporation into disulfide and lanthionine peptidomimetic opioids
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The synthesis of α-methyl amino acid building blocks and their incorporation into disulfide and lanthionine peptidomimetic opioids
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The synthesis of α-methyl amino acid building blocks and their incorporation into disulfide and lanthionine peptidomimetic opioids
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Dissertation
The synthesis of α-methyl amino acid building blocks and their incorporation into disulfide and lanthionine peptidomimetic opioids
2004
Overview
There are three main types of opioid receptors, μ, δ, and κ. While μ-selective agonists are efficient at producing potent analgesia, they produce a number of unwanted side-effects including respiratory depression, gastrointestinal inhibition, suppression of the immune system, and physical dependence. It has been our focus to synthesize δ-selective agonists which have been shown to have an improved side effect profile as compared to μ-selective agonists. Our goal was to develop peptidomimetic enkephalin analogs which retain the δ-potency of DPDPE but exhibit an increase in in vivo activity. A versatile enantioselective synthesis of α-methylcysteine was accomplished, and this peptidomimetic building block was incorporated into a family of disulfide enkephalin analogs. The disulfide analog with DPen in position two and α-MeDCys in position five ([DPen2, αMeDCys 5]E) was very δ-selective and an order of magnitude more potent than DPDPE in vivo. The analog with DCys in position two and α-MeDCys in position five ([DCys2, αMeDCys 5]E) is the most potent δ-selective enkephalin analog synthesized to date, with picomolar activity in vivo. Based on the biological activity of the α-methylcysteine containing disulfide enkephalin analogs, a family of lanthionine enkephalin analogs were designed and synthesized. In these α-methylcysteine containing enkephalin analogs the disulfide bridge was replaced with a thioether linkage. Two compounds exhibited promising biological activity. The first was [DPen2 L, αMeCys5L]E which was very δ-selective and two orders of magnitude more potent than DPDPE in vivo. The second was [DCys2L, αMeCys5 L]E which retained δ-selectivity but exhibited subnanomolar activity in vivo. A large scale synthesis of lanthionine enkephalin analog [DVal 2L, Ala5L]E was carried out in solution producing over 600 mg of HPLC purified compound. This δ-selective lanthionine enkephalin analog was evaluated as an analgesic in an osteosarcoma model in mice. It reversed tactile allodynia caused by the osteolytic osteosarcoma in a dose-dependent fashion. The δ-selective analog [DVal2 L, Ala5L]E was 4.5 times more potent than morphine in this model and exhibited a longer duration of action. This analog was reversed by naltrindole indicating that its analgesic effects are a result of interaction with δ-opioid receptors. Based on the successful enantioselective synthesis of α-methylcysteines, a versatile route to optically pure α-methyl amino acids was developed. The common intermediate is Bn2N-α-Me-Ser-β-lactone which is regioselectively opened with a wide variety of Grignard-derived organocuprates.
