The chemical and pharmacological importance of morphine analogues

Abstract

The object of this review is to summarize the efforts which resulted in the discovery of therapeutically useful morphine-like drugs. The search for new analgesics can be divided into three stages: (a) search for analgesics with high efficacy and reduced unwanted side-effects; (b) understanding of structure-activity relationships; (c) studies on the mechanism of pain perception and its alleviation by investigation of the pharmacology of opioids. An immense body of literature has been produced on the syntheses of thousands of new compounds which resulted in the development of detailed structure-activity relationships. The physical and psychologic dependence of opioid analgesics also facilitated investigators to solve the problem of the separation of strong analgesia from addiction liability. In the past decades more mixed agonist-antagonist analgesics, pure antagonists devoid of agonist action and potent opioids like the 6,14-ethenomorphinan derivatives were developed. Naloxone, Naltrexone, Buprenorphine and Pentazocine are the outstanding representatives which are introduced into clinical therapy.

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

“…1 Since the structure elucidation of morphine many years ago, its skeleton and its conversion to new analogues have been intensively explored. 2,3 Consequently, the morphinan skeleton (Figure 1) has been the basis of numerous drug developments, and several molecules with distinctive pharmacology are available for patient use or employed as molecular probes in vitro and in vivo. 2−4 The morphinan class of opioid analgesics includes naturally occurring alkaloids (e.g., morphine, codeine), semisynthetic derivatives (e.g., oxycodone, oxymorphone, buprenorphine), and synthetic analogues (e.g., levorphanol, butorphanol).…”

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

“…Structural variations at the N-17 of the morphinan skeleton have resulted in a diversity of compounds appraised as valuable and therapeutic agents and important research tools [3], [9], [11], [12]. Furthermore, discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one example of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6 [9], [39]. Taken together, in the present study we highlight on the significant outcomes of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging SAR.…”

“…Numerous highly potent morphine-like compounds are known, one of them being oxymorphone, a MOP agonist (Figure 1). Oxymorphone is used not only clinically [19], but also as a valuable scaffold for the development of new ligands interacting with the MOP receptor [9], [11], [20]. A representative example of the complex role played by the morphinan nitrogen in determining the pharmacological properties includes N-substituted derivatives of oxymorphone, ranging from potent agonism i.e.…”

Novel Treatment Strategies for Cocaine and Opioid Abuse

“…In spite of having an extensive side-effect profile, morphine, isolated from opium, remains the gold standard for treating chronic or persistent pain. Activation of the µ-opioid receptors located in the regions of brain and spinal cord that transmit pain are responsible for the majority of the physiological and behavioral effects of morphine [12][13][14] Morphine is a lipophilic compound and is available as sulphate, atartrate and hydrochloride salt. Morphine has been considered the drug of choice for treating moderate to severe pain.…”

“…The most prominent side effects are respiratory depression, decreased gastrointestinal motility and the development of dependence, withdrawal symptoms after chronic administration [16][17][18]. In therapeutic doses morphine also causes euphoria, sedation, nausea and vomiting [14]. One of the major side effects of morphine administration is development of tolerance to the analgesic effect [13].…”