paracelsius
Bluelighter
- Joined
- Mar 11, 2020
- Messages
- 197
No, actually they didn't stop at mice and rats tails: they tested it in rhesus monkeys! This as close a model to humans as it gets as far as CNS drugs concerned.
Here is what that the japanese study of this chem found: when initiate (1mg/kg) IVed to monkey (n=6), by day 3 the monkey will gladly volunteer not only to continue pushing the buttom to self-IV it to himself but escalate the dose every day and jack it up to a staggering 120 shots a day by day 21 (see fig 4 in ref). At day 21, if you replace the drug solution with saline, the animal will suffer debilitating withdrawals then resume self-administration when the drug is again available and jack up the dose to close to 300 (1mg/kg) shots per day!!! (see ref). Quite possibly one of the most addictive substance ever, with tolerance apparently developing very quickly (at least in monkeys!). Probably that is why the japanese didn't pursue this substance further. It is easy to see how humans would respond!!! at least the non-OP tolerant ones.
Now here is the interesting thing: at up to 20 mg/kg, parent unsubstituted Azabicyclane (anazocine) does not susbtitute for morphine in morphine-trained monkeys in withdrawal (unlike Pethidine?!?!!) meaning that it is probably either a weak opioid agonist or a mixed agonist-antagonist (in monkeys). But then the question is why is it so reinforcing and addictive at 1mg/Kg, 20 times lower dose than used above??
Well, the same study find that actually it is also A POTENT STIMULANT!!! (cross tolerance with stim).
I am not surprised. In my opinion, the beta conformer is a POTENT DNRI stimulant while the alfa is a mu-OP agonist. So mixture of the two stereoisomers will have DNRI activity AND mu-OP activity. It is not clear from the isomerization Rx the authors runs (mixture of alfa/beta + MeOH/acid--->beta), whether the product is the alfa or beta or a mixture of both. The preceding grignard Rx gives a 60:40 mix alfa:beta though. They mentioned that evidence for the isomerization is just by inference to similar compounds but no hard data to back it up. At that time (1970s), it was tedious work and lots of $$$ to determine that. So my guess is the product they tested in rhesus monkey was a mixture of a POTENT DNRI (the beta conformer with at least 10x cocaine) AND a POTENT mu-OPIOID AGONIST (at least 10X morphine for the alfa conformer at mu-opioid receptors). Basically the ultimate speedball!!!!!
I will post the reasons why I am saying that later + why the activity of the meta-hydroxy jacks up to 100s times morphine...
...sorry for the long post. (corona-lockdown where I live. which gave me too much time on my hands to write re: azabyclane OP-Stims).
edit: that paper is in japanese, but most of the interesting data caption + abstract is in english.
Oh BTW, a recent patent (2018 )on this SAME azabicyclo was published recently: nothing new really (they just add substituents to the phenyl ring with all kind of shit and claim "new" analgesics). but they do confirm same analgesic activity as previous papers though! (check it out)
Here is what that the japanese study of this chem found: when initiate (1mg/kg) IVed to monkey (n=6), by day 3 the monkey will gladly volunteer not only to continue pushing the buttom to self-IV it to himself but escalate the dose every day and jack it up to a staggering 120 shots a day by day 21 (see fig 4 in ref). At day 21, if you replace the drug solution with saline, the animal will suffer debilitating withdrawals then resume self-administration when the drug is again available and jack up the dose to close to 300 (1mg/kg) shots per day!!! (see ref). Quite possibly one of the most addictive substance ever, with tolerance apparently developing very quickly (at least in monkeys!). Probably that is why the japanese didn't pursue this substance further. It is easy to see how humans would respond!!! at least the non-OP tolerant ones.
Now here is the interesting thing: at up to 20 mg/kg, parent unsubstituted Azabicyclane (anazocine) does not susbtitute for morphine in morphine-trained monkeys in withdrawal (unlike Pethidine?!?!!) meaning that it is probably either a weak opioid agonist or a mixed agonist-antagonist (in monkeys). But then the question is why is it so reinforcing and addictive at 1mg/Kg, 20 times lower dose than used above??
Well, the same study find that actually it is also A POTENT STIMULANT!!! (cross tolerance with stim).
I am not surprised. In my opinion, the beta conformer is a POTENT DNRI stimulant while the alfa is a mu-OP agonist. So mixture of the two stereoisomers will have DNRI activity AND mu-OP activity. It is not clear from the isomerization Rx the authors runs (mixture of alfa/beta + MeOH/acid--->beta), whether the product is the alfa or beta or a mixture of both. The preceding grignard Rx gives a 60:40 mix alfa:beta though. They mentioned that evidence for the isomerization is just by inference to similar compounds but no hard data to back it up. At that time (1970s), it was tedious work and lots of $$$ to determine that. So my guess is the product they tested in rhesus monkey was a mixture of a POTENT DNRI (the beta conformer with at least 10x cocaine) AND a POTENT mu-OPIOID AGONIST (at least 10X morphine for the alfa conformer at mu-opioid receptors). Basically the ultimate speedball!!!!!
I will post the reasons why I am saying that later + why the activity of the meta-hydroxy jacks up to 100s times morphine...
...sorry for the long post. (corona-lockdown where I live. which gave me too much time on my hands to write re: azabyclane OP-Stims).
edit: that paper is in japanese, but most of the interesting data caption + abstract is in english.
Oh BTW, a recent patent (2018 )on this SAME azabicyclo was published recently: nothing new really (they just add substituents to the phenyl ring with all kind of shit and claim "new" analgesics). but they do confirm same analgesic activity as previous papers though! (check it out)
