Hello Bees, I have read with much intrigue ning's "OTC piperidone --> fentanyl" thread, and feel that is an interesting avenue of opioid research. Highly overlooked by the hive has been modifications to the oxymorphone molecule. When the 14-HO of oxymorphone is replaced with an alkyl group, this class of drugs is called the 14-alkoxymorphinans. The 14-alkoxymorphinans include some of the strongest opiates known to man such as 14-phenylpropoxymetopon (https://www.thevespiary.org/rhodium/Rhodium/pdf/14-phenylpropoxymetopon.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/14-phenylpropoxymetopon.pdf). The avenue I will investigate in this thread is the optimization of the production of oxymorphone, 14-methoxy-oxymorphone, and 5-methyl-14-methoxy-oxymorphone (14-methoxy-metopon (https://www.thevespiary.org/rhodium/Rhodium/pdf/14-methoxymetopon.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/14-methoxymetopon.pdf)).
Pharmacological Data:
14-Methoxymetopon, A Potent Opioid, Induces No Respiratory Depression, Less Sedation, and Less Bradycardia than Sufentanil in the Dog
Anesth. Analg. 1999, 88, 332.
http://www.anesthesia-analgesia.org/cgi/content/abstract/90/6/1359 (http://www.anesthesia-analgesia.org/cgi/content/abstract/90/6/1359)
14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 µg/kg) to awake, trained canines (n = 7).
14-Methoxymetopon, a very potent mu-opioid receptor-selective analgesic with an unusual pharmacological profile
Eur J Pharmacol. 2003 Jan 17;459(2-3):203-9
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12524147&dopt=Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12524147&dopt=Abstract)
14-Methoxymetopon is a potent opioid analgesic. When given systemically, it is approximately 500-fold more active than morphine. However, this enhanced potency is markedly increased with either spinal or supraspinal administration, where its analgesic activity is more than a million-fold greater than morphine.
Binding characteristics of [3H]14-methoxymetopon, a high affinity µ-opioid receptor agonist
European Journal of Neuroscience Volume 18 Issue 2 Page 290 - July 2003
http://www.blackwell-synergy.com/links/doi/10.1046/j.1460-9568.2003.02744.x/ (http://www.blackwell-synergy.com/links/doi/10.1046/j.1460-9568.2003.02744.x/)
To a solution of 7,8-didehydro-4,5-epoxy-3-hydroxy-14-methoxy-5,17-dimethylmorphinan-6-one (14-methoxy-5-methylmorphinon) (Schmidhammer et al., 1990) (1.68 mg, 5.1 µmol) in N,N-dimethylformamide (1 mL) PdO/BaSO4 (9.9 mg) was added. The mixture was stirred for 80 min in the presence of 555 GBq (15 Ci) of 3H2 and diisopropylethylamine (3.5 µL) at room temperature in a closed vacuum manifold (Tóth et al., 1996). The excess of 3H2 was removed by absorption on pyrophoric uranium. The catalyst was filtered off by use of a Whatman GF/C glass fibre filter. The labile 3H2 was removed by repeated evaporation with ethanol : water (1 : 1) affording 115 mCi of crude product. Purification of 60 mCi of the crude product by thin layer chromatography (Merck Kieselgel 60 F254 plate; eluent - dichloromethane : methanol : concentrated ammonia, 90 : 9 : 1) yielded 30.2 mCi of [15,16-3H2]-14-methoxymetopon with a specific radioactivity of 15.9 Ci/mmol and a purity of >95%.
Intrinsic efficacy and addiction to opioids
European Neuropsychopharmacology Volume 5, Issue 3 , September 1995, Page 403
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T26-4293HTX-RV&_coverDate=09%2F30%2F1995&_alid=133771035&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4910&_sort=d&view=c&_acct=C000000152&_version=1&_urlVersion=0&_userid=112642&md5=c7710df33addf01f827fc6355af75135 (http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T26-4293HTX-RV&_coverDate=09%2F30%2F1995&_alid=133771035&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4910&_sort=d&view=c&_acct=C000000152&_version=1&_urlVersion=0&_userid=112642&md5=c7710df33addf01f827fc6355af75135)
Tolerance to opiods is measured after 8 weeks for Fentanyl, 14-Methoxymetopon, morphine and 6-azido-dihydroisomorphine. Morphine developed 3 times more tolerance than the other 3 drugs.
Biochemical and Pharmacological Characterization of Highly Potent Novel Opioid Agonists in the 14-Alkoxymetopon Series
Eur. J. Pharmacol. 236: 209-215, 1993.
Opioid Binding Characteristics of 14-Alkoxy Derivatives of Methylmorphinan-6-ones
Analgesia 1995, 1, 590.
Characterisation of 14-O-Ethyl-5-methylnaltrexone: A Novel Opioid Receptor Antagonist
Br. J. Pharmacol. 109, 99 (1993)
Highly potent novel opioid receptor agonist in the 14-alkoxymetopon series
European Journal of Pharmacology Volume 236, Issue 2, 19 May 1993, Pages 209-215
http://dx.doi.org/10.1016/0014-2999%2893%2990591-5 (http://dx.doi.org/10.1016/0014-2999%2893%2990591-5)
The newly synthesized 14-alkoxymetopon derivatives, 14-methoxymetopon, 14-methoxy-5-methylmorphinone, exhibit high affinity for the naloxone binding sites in rat brain. A substantial decrease in affinity was observed, in the presence of NaCl indicating a high degree of agonist activity. All three 14-alkoxymetopon derivatives displayed high affinity for [3H][D-Ala2,(Me)Phe4,Gly-ol5]enkephalin ([3H]DAMGO) binding sites, much less potency toward sites and were the least effective at sites. Isolated tissue studies using the guinea pig ileum preparation confirmed their high agonist potency. Following administration the new compounds produced naloxone reversible antinociceptive effects and were 130–300 times more potent than morphine in the acetic acid induced abdominal constriction model in the mouse, and the hot plate and tail flick tests in the rat. The compounds also produced dose-dependent muscle rigidity, and potentiated barbiturate-induced narcosis. The in vivo apparent pA2 values for naloxone against 14-ethoxymetopon and morphine were similar in analgesia, suggesting an interaction with the same () receptor site. The dependence liability of 14-alkoxymetopon derivatives in the withdrawal jumping test was less pronounced than that of morphine in either rats or mice, similar to tolerance to the their analgesic action. It is concluded that the 14-alkoxymetopon derivatives studied are selective and potent agonists at opioid receptors, with reduced dependence liability.
Self-administration of 14-Methoxymetopon in rats
European Opioid Conference Uppsala, Uppsala, 2002
Effects of 14-methoxymetopon, a potent opioid agonista, on the responses to the tail electric stimulation test and plus-maze activity in male rats.
Brain Res. Bull. 57, 661-6
Signal transduction efficacy of the highly potent mu opioid agonist 14-methoxymetopon
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10809184&dopt=Abstract (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10809184&dopt=Abstract)
Life Sci. 2000 Mar 31;66(19):1871-7.
Synthesis data:
Patent US4362733 (http://l2.espacenet.com/dips/viewer?PN=US4362733&CY=gb&LG=en&DB=EPD)
14-alkoxymorphinans including a step by step procedure of methylation using methyl iodide and sodium hydride (Same as: EP0068382, CA1170654, JP58008068, DE3262036D)
Why this is important:
This means that one could treat 14-hydroxycodeinone with methyl iodide and sodium hydride, then hydrogenate to get the codeinone version of 14-methoxy-oxymorphone.
One could then demethylate this at the 3 position to get 14-methoxy-oxymorphone.
Could one treat oxymorphone (made from morphine obtained from pods) with Post 478120 (https://www.thevespiary.org/talk/index.php?topic=9741.msg47812000#msg47812000)
(Vitus_Verdegast: "To avoid having to make DMS", Methods Discourse) for substitutes)
These may be replaced with their ethyl versions to create 14-ethoxy-metopon.
My next posts will include a list of references regarding the 5-methylation of the morphinan skeleton, many novel 3-demethylation reactions for opiates (codone->morphone & codeine->morphine) including some OTC ones, an extraction of thebaine from poppy pods so simple mother nature could do it, an extraction of morphine from pods, and a comprehensive list of all possible routes within this branch of opiate chemistry.
Disclaimer: I am not a chemist, I have spent many hours researching this out of curiosity.
I forgot to mention in the first post that it also seems that any opiate can be 14-methoxylated or 14-ethoxylated yielding a more potent compound. Although the most studied compounds seem to be the derivatives of oxymorphone. This may turn out to be extremely useful in conjunction with Post 471554 (https://www.thevespiary.org/talk/index.php?topic=9690.msg47155400#msg47155400)
(merbst: "14-hydroxycodeinone -> oxymorphone !!!", Methods Discourse) my post in the methods forum regarding converting 14-hydroxycodeinone directly to oxymorphone. This would allow:
Step 1 - codeine phosphate to codeine freebase
Step 2 - codeine freebase to 14-hydroxycodeineone
Step 3 - 14-hydroxycodeinone to oxymorphone
Step 4 - oxymorphone to 14-methoxy-oxymorphone
For a realistic facile 4000X potency increase of codeine.
I will post in the near future references which indicate to me that it may be possible to use a more OTC acid such as HI or HCl in place of HBr in this reduction.
Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 1. Highly Potent Opioid Agonists in the Series of (-)-14-Methoxy-N-methylmorphinan-6-ones
J. Med. Chem. 1984, 27, 1575
https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/1%20-%20Highly%20Potent%20Opioid%20Agonists%20in%20the%20Series%20of%2014-Methoxy-N-methylmorphinan-6-ones.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/1%20-%20Highly%20Potent%20Opioid%20Agonists%20in%20the%20Series%20of%2014-Methoxy-N-methylmorphinan-6-ones.pdf)
Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 14. 14-Ethoxy-5-methyl Substituted Indolomorphinans with mu Opioid Receptor Selectivity
Bioorg. Med. Chem. Lett. 1997, 7, 151.
https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14%20-%20ethoxymetopon.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14%20-%20ethoxymetopon.pdf)
Behavioural effects of some non-quaternary ionisable derivatives of 14-methoxymetopon in rats
Addiction S392 P.5.017
https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14-methoxymetopon-less-abusable-ha.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14-methoxymetopon-less-abusable-ha.pdf)
Effects of 14-methoxymetopon, a potent opioid agonista, on the responses to the tail electric stimulation test and plus-maze activity in male rats.
Brain Res. Bull. 57, 661-6
https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14-methoxymetopon%20on%20tail%20electric%20and%20plus%20maze.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14-methoxymetopon%20on%20tail%20electric%20and%20plus%20maze.pdf)
Could some kind mod please allow me to tidy up the post at the top by fixing some links, and adding some more references?
Identification of Opioid Ligands Possessing Mixed µ Agonist/delta Antagonist Activity among Pyridomorphinans Derived from Naloxone, Oxymorphone, and Hydromorphone
Subramaniam Ananthan, Naveen K. Khare, Surendra K. Saini, Lainne E. Seitz, Jeffrey L. Bartlett, Peg Davis, Christina M. Dersch, Frank Porreca, Richard B. Rothman, and Edward J. Bilsky
J. Med. Chem. 2004, 47(6), 1400-1412 (2004) (http://www.streamload.com/scarmani/Opioids/Identification_of_Opioid_Ligands_Possessing_Mixed_Agonist_Antagonist_Activity_among_Pyridomorphinans_Derived_from_Naloxone_Oxymorphone_and_Hydropmorphone.pdf)
(http://www.streamload.com/scarmani/Opioids/Identification_of_Opioid_Ligands_Possessing_Mixed_Agonist_Antagonist_Activity_among_Pyridomorphinans_Derived_from_Naloxone_Oxymorphone_and_Hydropmorphone.pdf)
DOI:10.1021/jm030311v (http://dx.doi.org/10.1021/jm030311v)
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000479119-pyridomorphinan.jpeg).
Abstract:
A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a-k) were synthesized and evaluated for binding affinity at the opioid mu, delta, and kappa receptors in brain membranes using radioligand binding assays and for functional activity in vitro using [35S]GTP-gamma-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) and mouse vas deferens (MVD) smooth muscle preparations. The pyridine ring unsubstituted pyridomorphinans possessing the oxymorphone and hydromorphone framework displayed nearly equal binding affinity at the mu and delta receptors. Their affinities at the kappa site were nearly 10-fold less than their binding affinities at the mu and delta sites. Introduction of aryl substituents at the 5'-position on the pyridine ring improved the binding affinity at the delta site while decreasing the binding affinity at the mu site. Nearly all of the ligands possessing an N-methyl group at the 17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed agonist activity at the mu receptor with varying potencies and efficacies. In the [35S]GTP-gamma-S binding assays, most of these pyridomorphinans were devoid of any significant agonist activity at the delta and kappa receptors but displayed moderate to potent antagonist activity at the delta receptors. In antinociceptive evaluations using the warm-water tail-withdrawal assay in mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacies when administered by the intracerebroventricular route. Among the ligands studied, the hydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed mu agonist / delta antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard mu agonist morphine produces significant tolerance, repeated administration of the mu agonist / delta antagonist ligand 7h produced no tolerance. These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with mixed mu agonist / delta antagonist profiles and such ligands may have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence, and related side effects.