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PubMed1992

Antinociceptive properties of two alkylating derivatives of morphinone: 14 beta-(thioglycolamido)-7,8-dihydromorphinone (TAMO) and 14 beta-(bromoacetamido)-7,8-dihydromorphinone (H2BAMO).

This study investigated the antinociceptive properties of two alkylating derivatives of morphinone, 14 beta-(thioglycolamido)-7,8- dihydromorphinone (TAMO) and 14 beta-(bromoacetamido)-7,8-dihydromorphinone (H2BAMO) in the mouse tail-flick assay. Intracerebroventricular administration of either TAMO or H2BAMO produced short-term antinociception. Both TAMO and H2BAMO were 11.6-fold more potent than an i.c.v. administration of morphine. These effects were antagonized by the mu-selective antagonist, beta-funaltrexamine, but not by the delta-selective antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH. TAMO pretreatment from 8 to 48 hr produced a time-related, dose-dependent antagonism of morphine-induced antinociception without showing any agonistic effect. Pretreatment with TAMO for 24 hr antagonized antinociception produced by both H2BAMO and morphine, as well as TAMO itself, but not that of the delta-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) or U50,488, a kappa-selective agonist. In order to distinguish this antagonistic effect from cross-tolerance between TAMO and morphine, two mu agonists, [D-Ala2,N(Me)Phe4,Gly-ol]enkephalin (DAMGO) and H2BAMO, were chosen for comparison. A single i.c.v. pretreatment of DAMGO or H2BAMO, at a dose that had equivalent analgesic effects as TAMO, attenuated morphine-induced antinociception, reaching a maximal effect at the time of the disappearance of agonistic effects of DAMGO and H2BAMO and lasting up to 24 hr. Additionally, a 16-hr pretreatment with TAMO, but not DAMGO or H2BAMO, reduced the development of physical dependence to morphine at 24 hr after morphine pellet implantation. Therefore, this study demonstrated that both TAMO and H2BAMO act as mu opioid agonists to produce short-term antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1994

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone: mu-selective irreversible opioid antagonists.

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone (N-CPM-MET-CAMO) were tested in opioid receptor binding assays and in the mouse tail-flick test in order to characterize the affinity, selectivity and antinociceptive properties of these two compounds. Incubating bovine striatal membranes with either MET-CAMO or N-CPM-MET-CAMO produced a wash-resistant, concentration- and time-dependent inhibition of the binding of the mu-selective ligand, [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin, but with no change in delta or kappa binding. Preincubating membranes with N-CPM-MET-CAMO decreased the maximum binding value for [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin binding without changing the Kd value. In the mouse tail-flick assay, MET-CAMO and N-CPM-MET-CAMO did not produce any antinociception up to a dose of 100 nmol after i.c.v. administration. However, pretreatment of mice with either compound produced a time- and dose-dependent antagonism of morphine-induced antinociception. Analgesia mediated by delta or kappa opioids was not altered by either MET-CAMO or N-CPM-MET-CAMO at a dose of up to 100 nmol. The mu antagonistic effect of 1 nmol of MET-CAMO and N-CPM-MET-CAMO appeared at 8 hr and lasted up to 72 hr, with a maximal effect at 16 to 24 hr after i.c.v. administration. Pretreatment of mice with 1 nmol of MET-CAMO or N-CPM-MET-CAMO, given by i.c.v. administration at -24 hr, produced a rightward and downward shift of dose-response line of i.c.v. morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMedDate not supplied

Biotransformation of morphine to dihydromorphinone and normorphine in the mouse, rat, rabbit, guinea pig, cat, dog, and monkey.

Biotransformation of morphine to dihydromorphinone and normorphine was studied in several mammalian species. Free and total dihydromophinone, morphine, and normorphine in the urine were determined, as propionyl derivatives, with a gas-chromatographic technique. Dihydromorphinone was detected as a morphine metabolite in the acid-hydrolyzed urine of all species studied except the dog and morphine-dependent man. Normorphine in both free and conjugated forms was detected in the urine of all species studied. The degree of biotransformation of morphine to dihydromorphinone in the guinea pig did not change during chronic administration of morphine sulfate, 25 mg/kg, daily for 28 days. The small amounts of dihydromorphinone and normorphine produced as metabolites make it unlikely that they play any significant role in the modification of the pharmacologic effects of morphine.

Animals↗

PubMed1993

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone: a long-lasting mu-opioid receptor antagonist devoid of agonist properties.

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) suppressed morphine-induced antinociception but had no effect on antinociception mediated by delta- or kappa-opioid receptors after a single i.c.v. 1-nmol injection from 8 to 72 h before testing. MET-CAMO had no agonist effects in the mouse tail-flick assay in doses up to 100 nmol. MET-CAMO is the first N-methylated morphine derivative which shows such long-lasting mu-selective opioid receptor antagonism with no agonistic properties.

Analgesics↗

PubMed1994

14 alpha,14' beta-[Dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis (7,8-dihydromorphinone) and 14 alpha,14' beta-[dithiobis[(2-oxo-2,1- ethanediyl)imino]]bis[7,8-dihydro-N-(cyclopropylmethyl)normorphinone]: chemistry and opioid binding properties.

14 alpha,14' beta-[Dithiobis[(2-oxo-2,1-ethanediyl)imino]] bis(7,8-dihydromorphinone) (TAMO) (13) was synthesized by condensing 14 beta-amino-7,8-dihydromorphine (4) with acetylthioglycolyl chloride and hydrolyzing the resulting ester with mild base to give a mixture of the thiol 9 and the disulfide 13. Chromatography of the mixture resulted in conversion of the bulk of the thiol 9 to the disulfide 13 by air oxidation. The disulfide 13 was also prepared by condensing the tert-butyldimethylsilyl ether of 4 with the dithiodiglycolyl chloride and treating the resulting product with F- to give the desired product. The pure thiol 9 free of contamination with the disulfide was prepared by treating 13 with excess N-acetyl-L-cysteine and processing the reaction mixture without resorting to chromatography for purification. The corresponding N-(cyclopropylmethyl) nor compound 15 was prepared from the silyl ether 6 and acetylthioglycolyl chloride followed by hydrolysis, treatment with F-, and air oxidation. Incubation of bovine striatal membranes with 13 and 15 resulted in wash-resistant inhibition of the binding of the mu-selective peptide [3H][D-Ala2,(Me)Phe4,Gly(ol)5]-enkephalin (DAMGO). Incubation of membranes with mu but not kappa or delta ligands protected the mu binding sites from alkylation by 13 and 15. The wash-resistant inhibition of mu opioid binding was partially reversed by the addition of the reducing reagent dithiothreitol (DTT). A Scatchard plot of the effect of 13 and 15 on [3H]DAMGO binding showed that these affinity ligands caused a marked decrease in the Bmax value without affecting the Kd value. The wash-resistant inhibition of binding, the reduction in the number of binding sites, the partial reversal of wash-resistant inhibition of binding by DTT, and previously observed long-term antagonism of mu opioid receptors in vivo support the conclusion that 13 and 15 bind covalently to the mu opioid receptor.

Alkylation↗

PubMed1993

14 beta-[(p-nitrocinnamoyl)amino]morphinones, 14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogues: synthesis and receptor activity.

A series of 14 beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5 beta-methyl group, were prepared from 14 beta-aminocodeinones and 14 beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa opioid receptors were determined by radiolabeled binding experiments using bovine brain membranes. An analogous series of 7,8-dihydrocodeinones and morphinones was prepared and assayed in the same systems. The 3-methoxy derivatives 3 and 4 were more selective than the corresponding morphinones for the mu receptor. The 5 beta-methylcodeinones 25 and 27 had lower affinity at all receptors than the corresponding morphinones, but the 5 beta-methylmorphinones had affinities similar to the morphinones 5 and 6. A similar pattern was observed in the 7,8-dihydro series. Two compounds, 5 beta-methyl-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and N-(cyclopropylmethyl)-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET- CAMO), acted as nonequilibrium ligands in antinociception and membrane binding studies. In mice after icv administration, neither ligand showed any agonist activity but 8-24 h after administration both compounds acted as potent mu antagonists. A Scatchard plot of the effect of N-CPM-MET-CAMO on [3H]DAMGO ([3H]D-Ala2, (Me)-Phe4, Gly(ol)5] enkephalin) binding to bovine striatal membranes showed that there was a significant decrease in the Bmax value and a marginal effect on the Kd value suggesting that the number of binding sites was reduced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acetylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was observed.

Animals↗

PubMedDate not supplied

(8S)-(glutathion-S-yl)dihydromorphinone, a novel metabolite of morphine from guinea pig bile.

A novel glutathione-conjugated metabolite of morphine has been isolated from the bile of guinea pigs given morphine. The metabolite was separated by preparative HPLC on a reverse phase column (YMC-GEL C18) using methanol/water (1:4, v/v) as eluate and purified by HPLC on another reverse phase column (mu-Bondapak phenyl) using water/acetonitrile/trimethylamine/acetic acid (150:3:2:1, v/v) as a mobile phase. The unambiguous structure assignment of the metabolite was performed by fast atom bombardment mass spectrometry and 400 MHz fourier transform NMR spectrometric analysis, and it was identified as (8S)-glutathion-S-yl)dihydromorphinone, in comparison with the synthetic morphinone-glutathione adduct.

Animals↗

PubMed1996

Effects of the structurally novel opioid 14 alpha, 14' beta-[dithiobis [(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinone) on schedule-controlled behavior and thermal nociception in rhesus monkeys.

The in vivo pharmacology of the structurally novel opioid 14 alpha, 14' beta-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinon e) (TAMO) was examined in rhesus monkeys with assays of schedule-controlled behavior and thermal nociception. TAMO (0.032-1.8 mg/kg) produced dose-dependent decreases in response rates maintained under a fixed-ratio 30 schedule of food delivery (n = 3) and increases in tail-withdrawal latencies in a warm-water tail-withdrawal procedure (n = 3). Both the rate-decreasing and antinociceptive effects of TAMO (1.0 mg/kg) were maximal after 40 to 80 min and lasted at least 160 min. Pretreatment with the mu-selective opioid antagonist quadazocine (0.001-0.1 mg/kg) antagonized the effects of TAMO and shifted the TAMO dose-effect curves to the right. Schild analysis yielded in vivo apparent pA2 values (mean +/- S.E.M.) of 8.8 +/- 0.072 and 8.7 +/- 0.40 for quadazocine antagonism of the rate-decreasing and antinociceptive effects, respectively, of TAMO, which suggests that the effects of TAMO were mediated by mu-opioid receptors. In addition, quadazocine (0.1-1.0 mg/kg) reversed the behavioral effects of TAMO (1.0 mg/kg) when quadazocine was administered immediately after TAMO had attained its maximal effect. Twenty-four-hour pretreatment with 1.0 mg/kg TAMO did not significantly after the rate-decreasing or antinociceptive effects of fentanyl or the rate-decreasing effects of morphine. The dose-effect curve for morphine antinociception was shifted 4-fold to the right 24 hr after pretreatment with 1.0 mg/kg TAMO. However, 24-hr pretreatment with an equiactive dose of morphine (10.0 mg/kg) also produced a small (2-fold) but significant rightward shift in the dose-effect curve for morphine antinociception. Twenty-four-hour pretreatment with 1.8 mg/kg TAMO had no effect on the antinociceptive effects of U69,593 (0.0032-0.1 mg/kg). These results suggest that TAMO acts as a reversible mu agonist with a relatively slow onset and a duration of action and relative efficacy similar to those of morphine in rhesus monkeys. Twenty-four hours after TAMO administration, the highest doses of TAMO that could be safely administered produced little or no mu antagonist effects and no kappa antagonist effects.

Analgesics↗

PubMed1952