Pharmacology Oxa-iboga disrupts opioid pathways in animal models without causing cardiac toxicity

[Quasimoto]

Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models - Nature Communications

Ibogaine is a natural substance that interrupts opioid addiction but has cardiac risks. This article introduces novel ibogaine analogs that show reduced cardiac risk and enhanced neuroplasticity and therapeutic-like effects in models of opioid use disorder.

www.nature.com

"Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids – termed oxa-iboga – defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential."

I wasn't sure to tag this pharmacology or neuroscience... I guess it's both.

 

[Quasimoto]

Oxa-iboga even shows "superior efficacy" over ibogaine in disrupting opioid addiction (in animals)

 

[Neuroprotection]

Fascinating topic, thank you for posting this.
This could be something very promising, the extremely high selectivity for kappa opioid receptors makes these compounds quite unique compared to the parent compound ibogaine which hits the 5HT2A receptor generating classical psychedelic effects, as well as blocking the NMDA receptor which imparts strong disassociative effects.

It would be interesting to see if the Kappa selective OxoIboga alkaloids are hallucinogenic in humans as are most Kappa agonists. it should also be noted that strong kappa agonists have been shown to be highly dysphoric in humans and animals.
This could be problematic in human use, especially for addiction treatment, all those they could be a plausible tool at specific stages of the addiction/withdrawal syndrome. for example, whenever very strong cravings hit. furthermore, if it turns out that they can safely reset the reward system, kappa selective oxoiboga analogues could be used as a one-off treatment tool for addiction, where temporary strong dysphoria might be an acceptable trade-off under medical supervision.

 

[MedicinalUser247]

I didn't even notice this. We must of been thinking of the same topic.

 

[emkee_reinvented]

"temporary strong dysphoria" for some might be more then acceptable.
Especially those who endured longterm dysphoria due to drug abuse, or other things like anhedonia.
But I thinking maybe it might also has other possible indications as treatment for drug dependency.

Might also be usefull or leed to new compounds that can also be used for depression or trauma/ PTSD.

 

[Skorpio]

Damn that is a good paper!

They found no aversive or depression inducing effects using mouse behavioral paradigms, so I wonder it’s subjective effects in humans.

They characterized it at a whole host of receptors in addition to SERT, NMDA, 5HT2A, and the opioid receptors KOR, MOR, and DOR, finding it really only hits all three opioid receptors in a KOR >> MOR > DOR manner. They also found that it has a G-protein over beta arrestin 2 bias at both opioid receptors. The binding data is in the supplement (it’s linked at the very bottom of the paper; after the references)

Really thorough work, and I hope the compound makes it into humans without and catastrophes (though they certainly aren’t uncommon).

In the discussion they mention 7-MC and some other ibogaine analogs in human trials already, though one mentioned seemed only to be a 5-HT2a agonist, which didn’t produce sustained effects.

It’s really crazy what a single oxygen for nitrogen substitution can do to a molecule…