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). 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)).
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
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
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/
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
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
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
Life Sci. 2000 Mar 31;66(19):1871-7.
Synthesis data:Patent US4362733
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
https://www.thevespiary.org/rhodium/Rhodium/chemistry/methyliodide.html"%3B>%3Bmethyl