Methoxetamine is better than ketamine

Many would be interested in the recent work of Dr. Philip Portoghese. He has come up with a unique opioid molecule having the mu-opioid receptor agonist ligand {oxymorphone}at one end and a metabotropic GlutimateReceptor-5 inverse antagonist ligand {(2-methyl-6((3 methoxy phenol) ethynyl-pyridine}at the other end - tethered by a 4 carbon/ 22 atom splice so that both ends can bind simultaneously. The mixture of the two ligands given separately have an analgesic potency 15 times that of morphine. The heteromer made by splicing the two together has a, (believe it or not Ripley) an antinociceptive potency 3.6 million times that of morphine, no build up of tolerance over time, no "reward", "high" or potential for abuse, no respiratory depression AND maybe best of all, no noticable withdrawal symptoms on rapid cessation of administaration. I can understand how making an actual connection between the two receptors might have some potentiating of the opioid's efficeintcy but to increase of 250,000 times is more than Dr. Portoghese could ever have hoped for. Such a medication gives hope for those with pain of such intensity that non-lethal dosages of opioids on the market are insufficient. Its potential to replace the opioids currently cornering the market and adding to the list of drug addicts daily is of even greater potential. Imagine a patient who is finding that 40 mg/ day of oxymorphone is just not getting the job done and allowing return of function and being able to do normal activities being able to receive the pain relief he actually needs from just 5 or 10 mcg of Dr. Portoghese'e MMG-22. Reread this last sentence and, yes that is really supposed to read 40 MILLIGRAMS vs. 5-10 MICROGRAMS. Seeking more information - try Googling Dr. Philip S. Portoghese and/or MMG-22 or just write me at ifyoucannotcall@writeme.com. If you ask me, the Sackler brothers should fund Dr. Portoghese in bringing this to market considering the tens of billions of dollars they made creating drug addicts with Oxycontin. Let Dr. P keep the patents and half the profits towards expanding research and facilities for such at University of Minnesota; and, the other half towards building and funding addiction rehabilitation centers for those that Purdue was at least in part to blame for.

 

Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11595-9. doi: 10.1073/pnas.1305461110. Epub 2013 Jun 24.

Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception.
Akgün E[SIZE=.8461em]1[/SIZE], Javed MI, Lunzer MM, Smeester BA, Beitz AJ, Portoghese PS.


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Abstract

The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR5) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR5 in glia and neurons, together with reports that suggest coexpressed MOR/mGluR5 receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR5 antagonist pharmacophores linked through spacers of varying length (10-24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED50 ∼9 fmol per mouse), whereas in untreated mice its ED50 was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ≥500-fold higher ED50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR5 heteromer. The finding that MMG22 possesses a >10(6) therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.

 

NATURE REVIEWS DRUG DISCOVERY | RESEARCH HIGHLIGHT

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G PROTEIN-COUPLED RECEPTORS

A double attack on pain

• Charlotte Harrison

Nature Reviews Drug Discovery



12,

[SIZE=14.495px]665[/SIZE][SIZE=14.495px](2013) [/SIZE][SIZE=14.495px]doi:10.1038/nrd 4105[/SIZE]

Published online:

[SIZE=14.495px]19 August 2013[/SIZE]


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Increasing evidence suggests that G protein-coupled receptors (GPCRs) can exist as heteromeric complexes with pharmacological properties that differ from the individual GPCRs. Two recent studies published in PNAS show that ligands targeting a heteromer consisting of the μ-opioid receptor (the target of the analgesic morphine) and a second GPCR could overcome some of the limit

 

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Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR[SIZE=.8em]5[/SIZE])

Eyup Akgün[SIZE=.8em]*[/SIZE]†, Muhammad I. Javed†, Mary M. Lunzer†, Michael D. Powers†, Yuk Y. Sham‡, Yoshikazu Watanabe†, and Philip S. Portoghese[SIZE=.8em]*[/SIZE]†

[SIZE=.8em]†[/SIZE]Department of Medicinal Chemistry, and [SIZE=.8em]‡[/SIZE]Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, United States

J. Med. Chem., 2015, 58 (21), pp 8647–8657
DOI: 10.1021/acs.jmedchem.5b01245
Publication Date (Web): October 09, 2015
Copyright © 2015 American Chemical Society
*(E.A.) Phone: 612-624-1988. E-mail: akgun001@umn.edu., *(P.S.P.) Phone: 612-624-9174. E-mail: porto001@umn.edu.




Abstract


Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR[SIZE=.8em]5[/SIZE] heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR[SIZE=.8em]5[/SIZE] antagonist pharmacophores linked through homologous spacers (14–24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED[SIZE=.8em]50[/SIZE] = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was tousands of times more potent than a mixture of mu agonist and CCR[SIZE=.8em]5[/SIZE]antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR[SIZE=.8em]5[/SIZE] heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR[SIZE=.8em]5[/SIZE] heteromer as a novel target for the treatment of chronic pain.

 

oh god, I love this shit. In all my experimentation, I have yet to find a hole. Unlike K, I feel super light and coordinated on this shit, and, though my thoughts drift more than baseline, I find each one to be clearer.

as far as disso's go, MXE is magic IMPO. It's a shame it's so much harder to get than it used to be. I remember $25/g >90% before China banned it. Also, I've found that while K attenuates a roll, MXE makes it trippier.

edit: don't get me wrong, K is awesome, but MXE is a more functional headspace for me

 

I've explored 2F-Ketamine a few times recently, a novel research chem which has I enjoy quite a bit. It has some similarities to MXE and Ketamine, probably residing between the two, closer to the Ketamine end of the spectrum. However, one drawback is the price is quite expensive compared to what MXE used to cost and the potency dosage wise and duration of 2F-Ket is more like that of Ketamine proper, so it's definitely easy to go through it really quickly.

That being said, I think the day after 2F-Ketamine is much more forgiving than Mxe and it's perhaps a bit more emotional oriented than Ketamine proper. I probably haven't quite reached as mind blowing levels as I have on the other two, but I haven't necessarily set my setting conducive to that yet, still I find this chem very intriguing and satisfies a lot of the desirable qualities I look for in dissociatives.