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

Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the mopioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics

On the role of peripheral sensory and gut mu opioid receptors: Peripheral analgesia and tolerance

There is growing evidence on the role of peripheral \ub5-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, \u3b2-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance

Antinociceptive activity of a novel buprenorphine analogue

HS-599 is a didehydroderivative of buprenorphine that displays high affinity and good selectivity for it-opioid receptors. We studied its antinociceptive properties after s.c. injection in mice with the tail-flick and hot-plate tests. In the tail-flick test HS-599 (AD(50) = 0.2801 mumol/kg s.c.) behaved as a full agonist and was twice as potent as buprenorphine (AD(50) = 0.4569 mumol/kg s.c.) and 50 times more potent than morphine (AD(50) = 13.3012 mumol/kg s.c.). Whereas the mu-opioid receptor antagonists naloxone (1 - 10 mg/kg s.c.) and naltrexone (5-15 mg/k- s.c.) antagonized HS-599 induced analgesia, the delta-opioid receptor antagonist naltrindole (20 mg/kg s.c.) and the n-opioid receptor antagonist nor-binaltorphimine (20 mg/kg s.c.) did not. With the hot-plate test at 50degreesC, HS-599 (AD(50) = 0.0359 mumol/kg s.c.) was a full agonist about 130 times more potent than morphine (AD(50) = 4.8553 mumol/kg s.c.). With a high intensity nociceptive stimulus (55degreesC) HS-599 (AD(50)= 1.0382 mumol/kg s.c.) remained 7 times more potent than morphine (AD(50) = 7.0210 mumol/kg s.c.) but never exceeded the 55% of the maximum possible effect, behaving as a partial agonist able to antagonize morphine antinociception in a dose-dependent manner. HS-599 promises to be a potent and safe new analgesic, preferentially acting at spinal level

14-Methoxymetopon, a highly potent micro opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats.

Rationale Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective mu opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index. Objective To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats. Methods Male sP rats with continuous 2- bottle choice access to ethanol (10% v/ v) or water were subjects. The effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 mu g/ kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 mu g/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 mu g/ kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 mu g/kg, s.c.) on self- administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003-100 ng, i.c.v.) on 4-h ethanol intake were evaluated. Results Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer- lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrex-one-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose response function, increasing it at a 10 pg dose, while suppressing it at a 10,000-fold higher dose. Conclusions The novel mu analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain mu opioid receptor stimulation on ethanol intake

SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 18,19-DEHYDROBUPRENORPHINE

18,19-Dehydrobuprenorphine (2) was prepared in five steps starting from thevinone (3) which is readily available from thebaine by Diels-Alder reaction. Grignard reaction with tert-BuMgBr afforded tert-butylthevinol (4) which was N-demethylated via N-cyano-tert-butylthevinol (5) using BrCN. Alkali treatment gave N-nor-tert-butylthevinol (6) which was alkylated with cyclopropylmethyl bromide to give N-cyclopropylmethyl-tert-butylthevinol (7), followed by ether cleavage with thiolate to yield 2. 18,19-Dehydrobuprenorphine displayed in opioid receptor binding studies very high affinity for mu receptors, while the affinity for kappa and delta receptors was lower. In the tail-flick test in mice, compound (2) was 25 times more potent than morphine and ca. 2.5 times as potent as buprenorphine