morphinans and 4-5-epoxymorphinan

14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexone) have become among the most important clinical agents to have been produced from opium. 14-Aminocodeinone and its 7,8-dihydro and morphinone derivatives are of more recent origin thanks to the work of Professor Gordon Kirby and his collaborators. The 14-amino parent compounds have proved of limited interest but their 14-acylamino- and 14-alkylamino derivatives have been extensively studied. The 4'-substituted cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones, C-CAM and M-CAM are the best available selective MOR irreversible antagonists and the related dihydrocodeinone MC-CAM, 4'-chloro-cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronorcodeinone, is a long-acting MOR partial agonist with extended MOR-pseudoirreversible antagonist activity that could be a candidate for pharmacotherapy of opiate abuse/dependence.

Topics: Animals; Humans; Morphinans; Structure-Activity Relationship

The 14-position of natural opiates (e.g. morphine) are unsubstituted, however synthetic approaches have uncovered that functionalizing position 14 gives rise to a wide range of diverse activities. This review focuses on SAR of the position, with the aim of aiding in the search for opioid analgesics with improved clinical profiles.

Topics: Animals; Humans; Morphinans; Narcotic Antagonists; Pain; Receptors, Opioid; Structure-Activity Relationship

To investigate the contribution of hydrogen bonding between the 14-hydroxy group and the 6-amide chain on the binding affinity of nalfurafine toward KOR and OX

Topics: Dose-Response Relationship, Drug; HEK293 Cells; Humans; Molecular Structure; Morphinans; Orexin Receptors; Receptors, Opioid; Structure-Activity Relationship

The orexin 1 receptor (OX

Topics: Dose-Response Relationship, Drug; Humans; Molecular Structure; Morphinans; Orexin Receptor Antagonists; Orexin Receptors; Structure-Activity Relationship; Sulfonamides

We re-examined the accessory site of the 4,5-epoxymorphinan skeleton by camdas conformational analysis in an effort to deign novel delta opioid receptor antagonists. We synthesized three novel compounds (SN-11, 23 and 28) with a 10-methylene bridge and without a 4,5-epoxy ring. Among them, compounds SN-23 (17-isobutyl derivative) and SN-28 (17-methyl derivative) showed very strong agonist activity (over 10 times more than TAN-67). SN-28 also showed high delta selectivity. The delta agonist activity of SN-23 was weaker than that of SN-28, but in terms of the delta selectivity, SN-23 was higher than that of SN-28. These unexpected results indicated that the 4,5-epoxy ring, but not the 10-methylene bridge, was an accessory site in delta opioid receptor agonists.

Topics: Drug Design; Morphinans; Naltrexone; Receptors, Opioid, delta

[reaction: see text]. A method was found for the novel synthesis of ortho ester derivatives that are potentially useful as selective epsilon opioid receptor ligands. An unexpected 17-(cyclopropylmethyl)-4,5alpha-epoxy-6alpha-hydroxy-3,7,7-trimethoxy-8-oxa-6,14-endoethanomorphinan was produced when 17-(cyclopropylmethyl)-4,5alpha-epoxy-3-methoxy-6alpha,14-dihydroxy-6beta-(1,3-dithia-2-yl)-morphinan was treated in methanol with trimethyl orthoformate and CuO/CuCl2. This ortho ester derivative was then converted to an ester with acid. The structure of the ortho ester was determined by 2D NMR (HMBC) and mass spectra.

Topics: Esters; Magnetic Resonance Spectroscopy; Molecular Structure; Morphinans; Stereoisomerism

Opioids, such as morphine, can directly alter immune function via receptors expressed on immunocompetent cells. However, several studies have questioned the classical opioid nature of this change in immune response. Therefore, it is unclear how opioids that are not from the same structural class as morphine (4,5-epoxymorphinan), will modulate the immune system, if they do not behave in a classical opioid manner. Therefore, the aim of this study was to investigate the in vitro modulatory effects of a range of non-4,5-epoxymorphinan opioids on splenocyte proliferation and compare the response characteristics to their central opioid characteristics. The modulation of concanavalin A stimulated mouse splenocyte proliferation by non-4,5-epoxymorphinan opioids resulted in three types of responses: an inhibitory concentration-response curve (e.g. methadone, inhibitory EC(50)=79.4 microM), an inverted bell shaped curve (e.g. fentanyl, inhibitory EC(50)=0.06 microM) and an induction concentration response curve (e.g. nor-binaltorphimine, induction EC(50)=0.16 microM). Non-stereoselectivity, naloxone-insensitivity, naloxone-sensitivity and non-classical opioid rank order of effect were all observed. These data support the non-classical opioid nature of direct opioid modulation of splenocyte proliferation.

Topics: Animals; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Morphinans; Narcotics; Opioid Peptides; Spleen

Morphine belongs to the class of compounds known as 4,5-epoxymorphinans, which can alter immune function directly via receptors expressed by immune cells. However, the opioid characteristics of these receptors are not clear. Therefore, the aim of this study was to investigate the in vitro immunomodulatory effects of 24 structurally related 4,5-epoxymorphinans to allow further characterisation of the receptor that mediates the immunomodulation and to ascertain if there is any structure-effect relationship. The immunomodulation of 4,5-epoxymorphinans using isolated mouse splenocytes stimulated with concanavalin A resulted in five types of responses: an inverted bell shaped curve (oxycodone, inhibitory EC(50)=1.6 nM), an inhibitory concentration response curve (buprenorphine, inhibitory EC(50)=12.6 microM), an inverted bell-shaped curve with induction (morphine, induction EC(50)=1.7 microM), an induction concentration response curve (oxymorphone, induction EC(50)=20 nM), and the lack of any response (e.g. noroxycodone). Non-stereoselectivity, naloxone-insensitivity, naloxone-sensitivity and non-classical opioid rank order of effect were all observed. A structure-effect relationship was developed and significant evidence for non-classical opioid receptor function on immune cells was concluded.

Topics: Animals; Cell Proliferation; Dose-Response Relationship, Drug; Immunologic Factors; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Mitogens; Morphinans; Naloxone; Narcotic Antagonists; Receptors, Opioid; Solutions; Spleen; Stereoisomerism; Structure-Activity Relationship