Norbinaltorphimine

2023-10-12: Drugs

Norbinaltorphimine (nor-BNI) #

• Selective κ-Opioid Receptor antagonist (“collateral agonist eficiency”)
  • No upregulation found in the rodent studies. Agonists however do downregulate. μ and δ antagonists show upregulation.
    • I think this is because it’s a channel blocker maybe?
  • Brendan: it acts like a partial agonist in a small portion of the receptor, which allows for JNK to build up within the receptor, which traps it in a desensitized state for an even longer duration.
    • Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal Kinase
      • Our present results support the classification of long-acting KOR antagonists as collateral agonists for the c-Jun N-terminal kinase (JNK) cascade.
      • 28 days after injection, residual norBNI effects were absent. (even though norbni itself stops binding at 8 days.)
    • JNK activation which increases and then traps the kors in a desensitized state even after clearance, which extends the duration of the antagonism and may cause some inflammation itself
• Guy on reddit says it needs to be paired with an NLRP3 antagonist like Berberine, since κ-Opioid Receptor antagonism on Microglia prevents it from repressing inflammatory signals (which can cause dopaminergic dysfunction). Brilliant Blue G seems even more powerful for that.
• Possibly cytotoxic? I think people say this due to the JNK activation. The question is, how much is it eliciting?
  • Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation
    • Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase
      • kappa opioid receptor activation by dynorphin and mu opioid receptor activation by morphine also activate c-Jun Kinase without documented adverse effects. Thus, physiological levels of c-Jun Kinase activation at the low pharmacological doses necessary may not have the toxic effects noted with intense activation*
• Systemic kappa opioid receptor antagonism accelerates reinforcement learning via augmentation of novelty processing in male mice
  • Enhanced novelty learning to both positive and negative stimuli without affecting the innate response to reward, so prob not producing conditioned place preference.
• Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion advancing dyskinesia would be evidence of enhanced D1 dominance.
• Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats
• Not sure how it’s serotonergic. Could be p38, maybe ERK or something.
• Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters
  • Besides κ, a 20 Ki at δ and 41 at μ are the only other relevant things.

Dose #

• Source: PGLchem or Chemyo
  • if you get the norbni solution from pglchem that is undiluted wear gloves when transferring it and diluting it. I got a drop of the undiluted solution on my hand and had a very uncomfortable two hours. Diarrhea, changes in body temp and uncomfortable cardiac sensations. I’m fine now though.
  • Brendan boiled his for ~2 minutes to get solution
• Intranasal produces week-long effects: Pharmacokinetic evidence for the long-lasting effect of nor-binaltorphimine, a potent kappa opioid receptor antagonist, in mice
• Low bioavailability but that may just be oral
• Brendan: anxiolytic, increased locomotion, focus, motivation, drive, reward, but no hedonistic or compulsive behavior. I recommend it and would even say that its one of my favorites. A bit of childlike curiosity too?
  • Norbni has quickly made its way to my number 1 favorite. It is more anxiolytic than bromantane I think, very chill and slightly stimulating. I can definitely feel quality dopaminergic and testosterone effects, both mentally in terms of solid motivation, drive, curiosity, dominance, less bothered by things, better mood etc, and in libido, especially erections. Basically, norbni just feels cleaner than bromantane, and I don’t mean to say anything bad about bromantane at all, because it has been my favorite for the past 2 years and I loved it….. But norBN**I seems to provide a clearer headspace, amplifies passion and enjoyment, and enhances resistance to stressors. On the other hand, bromantane has helped me tremendously in pushing through stressful times but it just lacks the same level of enjoyment, passion, and curiosity that norbni offers.
  • Dosed weekly at the most @ 200 μg.
• TM: Would be perfect if it didn’t make his heart race at 2AM
  • Gave him terrible side effects (140BM, sweating, nausea, confusion, teeth clenching) for a week straight on 500-600 mcg when combined with pinealon (double whammie) and he also took kanna at some point
    • There’s also that guy who got a backout where he lost memory of the past several months on norBNI + MAOA-Is but
• JC: Zero negative affect. Bad stuff happens and it registers, but theirs like no physiological response. I just immediately start working toward fixing it. I believe it promotes active coping.
• Uxkull: Due to his MAO-A polymorphism, him and TM got symptoms of serotonin syndrome when combining with Kanna.

Let’s go with 100mcg/spray to be safe. I got 15mg in this vial at 1.5mL so 10mg/mL, and I want 1mg/mL which = 100mcg/spray. Add 13.5mL of water to do so and voila