One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (μ, δ, κ), the μ (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are agonists at the MOR and are the mainstay for the treatment of moderate-to-severe pain. However, adverse effects related to opioid use are severe and often lead to early discontinuation and inadequate analgesia. The development of more effective and safer medications for the management of pain still remains a major direction in pharmaceutical research. Chemical approaches towards the identification of novel MOR analgesics with reduced side effects include structural modifications of 14-alkoxy-N-methylmorphinan-6-ones in key positions that are important for binding, selectivity, potency, and efficacy at opioid receptors. This paper describes a representative strategy to improve the therapeutic usefulness of opioid analgesics from the morphinan class of drugs by targeting position 5. The focus is on chemical and biological studies and structure-activity relationships of this series of ligands. We report on 14-alkoxymorphinan-6-ones having a methyl and benzyl group at position 5 as strong opioid antinociceptive agents with reduced propensity to cause undesired effects compared to morphine although interacting selectively with MORs. 1. Introduction The analgesic action of extracts of the opium poppy plant Papaver somniferum has been recognized for centuries. Morphine (Figure 1), the primary active component of opium, was isolated in 1805 by the German pharmacist Friedrich Sertürner, and more than 120 years elapsed when Gulland and Robinson proposed its correct structure [1]. Today, opioid analgesics play a central role in pain control and are generally considered to be highly effective in the management of moderate-to-severe pain [2, 3]. They can be classified into three classes: natural derivatives occurring in opium such as morphine and codeine; partially synthetic derivatives, including hydromorphone, oxycodone, oxymorphone, and buprenorphine; and synthetic compounds such as levorphanol, butorphanol, fentanyl, sufentanil, and the recently introduced tapentadol (Figure 1) [3–5]. Figure 1: Examples of clinically used opioid analgesics. Opioids act on three G-protein-coupled receptors (GPCRs) that is, μ (MOR), δ (DOR), and κ (KOR) [6], but it appears that the analgesic action of the most commonly used opioid analgesics is mediated primarily via the MOR. Activation of MORs, widely expressed in the
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