Possible Drugs of the Future

[Dope_User]

As everyone knows, pharmaceutical companies pour billions into their research and development programs and new drugs are being developed all the time (whether they are effective at what they where designed for or whether or not they make it to market is another story).

I'm wondering if any research has been done or is currently going on regarding opioids of the future. Obviously, I'd like to see one with the rush that lasts for hours with no physical addiction (with anything like that, psychological addition would be incredible intense. But back to the topic, does anyone know of R&D work going on in the field of opioids? Possibly even related to the treatment of opioid addiction (Bupe is gaining popularity where all you used to hear about was methadone)?

Links to scientific journals and articles are greatly appreciated.

P.S. If you feel like mentioning other "mind altering" drugs in development, feel free, but please try to keep it to opioids.

 

[fastandbulbous]

Not an R&D development target

I can't see Pfizer or SmithKlineGlaxo (or whatever the fuck they call themselves now) spending all the R&D money on developing an opiate with a better, longer rush (I know, someone should).

I'll cobble together a quick piece about the different chemical families of opiates, and which ones the clandestine chemist might want to do his (or her) own "R&D" on, if anybody's interested

 

[Smyth]

There was recently a good article about piperazine narcotics that I saw on that site, you know that one where it has a picture of a bumble bee. I actually already have a research regime for the invention of a novel narcotic analgesic. The problem is that due to financial constraints it will be some time before it gets underway. I should have thought that it will have been accomplished before the end of this decade though.

 

[Dope_User]

fastandbulbous, that would be great. I was just saying I wished for that type of opioid, not that anyone was actually making it...just wondering what they're working on.

 

[BilZ0r]

They work on pain killers that aren't addictive...

 

[mitogen]

IMO, there are plenty of useful opioids around...
the name of the family of proteins eludes me right now, but they increase the intrinsic GTPase activity of g-proteins, leading to faster signal termination. you can block the active site of these proteins (where they bind g-proteins.) they are expressed regionally as well which gives a lot of specificity.
basically it means that you need to have a much smaller opioid concentration at the receptor site to get the same effect. if you add an inhibitor to an opiod, there will be much less binding to undesirable targets (eg centres involved in itching! ARHHg) and also possibly less tolerance

 

[tantric]

1)The coke cartels will hire some chemists and start making new, MUCH more powerful versions of cocaine. They are out there, the research exists, it's just that you need coke or ecgonine to start with. Look for this soon. If they were hiring, I'd go in a sec! Hell, even Dr. Shulgin might be tempted. Also, look for coke being grown in new parts of the world, like Indonesia, etc.

2)Weird shit based on ibogaine - this is a whole class of drugs, most of them dissociatives. Actual ibogaine is almost impossible to make, but some of the stuff from Voacanga could be harvested with about the same level of difficulty as cocaine. Africa is too poor to turn down such an opportunity. Wouldn't you LOVE to be able to buy voacangamine on the street?

3)LOTS of new types of GHB. GHB is only slightly harder to make than meth, just as addictive, and the precursors are uncontrollable.

4)probable return of fentanyl. Overseas labs are getting more sophisticated, and this is the most power opiate possible. a kilo of fent would be worth millions.

 

[mik82]

3)LOTS of new types of GHB. GHB is only slightly harder to make than meth, just as addictive, and the precursors are uncontrollable.

Surely GHB is easier to make - all you need to do is mix "A" and "B" in aqueous ethanol with a bit of pH testing? All you're doing is ring opening a lactone. And in what way is it just as addictive as meth?

 

[Riemann Zeta]

I would estimate that the first large paradigm shift will be the demise of methylamphetamine in the US. I hear that ephedrine is going to become emergency scheduled such that individuals over 18 yrs. of age may only purchase one box per month, or something along those lines. After methylamphetamine goes away, (dl)-amphetamine sulfate and (d)-amphetamine sulfate--manufactured mainly in former soviet states--will make a dramatic return, like in the EU.

Also, the demise of opioids as we know them is a likely possibility. Obviously, hospitals will have them in case of emergencies, but they will be kept locked up. All opioids given on an outpatient basis will be closely monitored and 'abuse'-proof: they will contain an opioid antagonist like naloxone to prevent IV/IM/nasal use and a small amount of an orally active antagonist, like naltrexone, to limit euphoria and help prevent tolerance. In addition, all 'strong' opioid pills will contain RFID tags to allow police to scan the population and determine if anyone is carrying a large number of pills. As such, there will an increase in clandestine synthesis of stronger opioids starting with codeine (i.e. codeine-->morphine/hydromorphone/hydrocodone). Also, I think someone will come up with something clever to turn loperaminde into a centrally-active opioid, leading to another ephedrine/methylamphetamine debacle, as junkies try to purchase 45 boxes of loperamide, claiming they have the shits.

In the stimulant domain, look for a huge rise in popularity of modafinil and various diphenylsulfonate derivatives as the world becomes more 24/7 and careers become ever more demanding. In tandem, I would think that time-release upper/downer combos will become popular for people who want to regulate their circadian rhythm. I could see 12hr/8hr, 16hr/6hr and 20hr/4hr upper/downer pills (in which the downer has a super-quick pharmacokinetic profile).

In the far far future (after we're all dead and rotting), look for direct brain stimulation to enter the euphoriant picture.

 

[ssmurphss]

The coke cartels will hire some chemists and start making new, MUCH more powerful versions of cocaine.

I heard something in the news about a new form of cocaine. Not too sure about where it originated, etc.

I would personally like to see a higher potency marijuana strain to come out. But just tell that to the govt. when they allow only strict limited testing because its illegal.

Just another question to throw out there:
Do you think oxycontin will be replaced in the near future, or are there plans underway to do such?
I've just heard about the flaws in oxycontin - how it was designed to not be abused, but it obviously didnt work.

 

[fastandbulbous]

Something clever...

Also, I think someone will come up with something clever to turn loperaminde into a centrally-active opioid

It doesn't take anything clever; it's the tertiary OH group that's preventing it crossing the blood brain barrier (the amide function must pass, otherwise dextromoramide wouldn't be centrally active). If you have a look at the attached jpeg, the answer to making it cross the blood brain barrier is the structure in red (makes it similar to the prodines - reverse ester pethedine)

 

[Dope_User]

fast, how difficult would it be to chemically alter loperamide in the way you are suggest? Say in terms of difficulty compared to converting morphine to heroin? Not that I'm about to experiment, but others may want to do something similar to buying ephedrine/pseudoephedrine to make meth...if it's not too complicated that it. Then we could have a new (potentially cheap and potent) black market opioid floating around.

 

[rivered1]

fastandbulbous: if it doesnt take anything clever and a solution is worked out then why hasnt it been done yet?

 

[Smyth]

This is nothing revelationary. Remember I pointed this out with tramadol almost 1 year ago? However someone was quick to dismiss it even though evidence to prove this was not forthcoming. It doesnt actually matter what the enzyme shows because this is only the pro-drug. In-vivo the ester is supposed to get hydrolysed but only after it has passed the BBB. Then since the hydroxy is not good at passing the BBB, it cannot get back out again easily. This is a neat little trick for modifying a drugs phamacokinetic properties.

 

[Dope_User]

Smyth, can you clarify that for me (not sure if you were talking about loperamide or tramadol)? And what did you point out a year ago about tramadol (I wasn't around then)?

 

[ebola?]

>>All opioids given on an outpatient basis will be closely monitored and 'abuse'-proof: they will contain an opioid antagonist like naloxone to prevent IV/IM/nasal use and a small amount of an orally active antagonist, like naltrexone, to limit euphoria and help prevent tolerance.>>

I posed this question in other drugs...but, to reiterate. How would the low-dose antagonist work like this in an analgesic? It is my understanding that the analgesic effect from opiates is largely mediated via mu agonism, so, in addition to curbing euphoria, the antagonist would also curb analgesia.

ebola

 

[Smyth]

I just merely pointed out that tramadol could be made more potent. Infact a fresh brand new patent on tramadol was out only say 2 month ago. That reminds me. I forget what they did exactly, but they were milking the cow out of tramadol! I mean the compounds they were pulling were ridiculously potent. I think they were making meta-hydroxy tramadol ie. the O-desmethyl derivative but I am not sure. I will have to check this out.

On a second note, I too read somewhere that opiate tolerance could be reversed but I dont know where and what exactly. I remember because I certainly raised my eye-brow's to it at the time of reading. This was about 6 months ago.

 

[Dope_User]

About opiate tolerance being reversed, check out the thread that was in OD (I think) called "Oxytrex" or something like that. It seems to be an opiate (probably oxycodone time released) combined with a small dose of an antagonist. In Phase III of clinical trials...check it out.

 

[Riemann Zeta]

I have never really looked in to the structure-activity relationships of loperamide derivatives, so thanks fastandbolbous. I knew that the p-glycoprotein transporter prevented loperamide from accumulating in the central nervous system and that MDR p-glycoprotein transporter knockout animals exhibit opioid-like effects from loperamide administration (e.g. Schnikel et al, 1996).

Anyone want to do a Fisher esterification with some acetic acid and some loperamide and test it out (I don't like opioids, so it would be lost on me)?

How would the low-dose antagonist work like this in an analgesic? It is my understanding that the analgesic effect from opiates is largely mediated via mu agonism, so, in addition to curbing euphoria, the antagonist would also curb analgesia.

Interesting question. There are some compounds out there that are delta and kappa opioid receptor agonists, with relatively weak activity at the mu receptor that are still antinociceptives in animal models. The mu receptor seems most tied to euphoria, so partly blocking the mu while agonizing the delta and kappa receptors could result in moderate analgesia with little euphoria (due to mixed mu agonist/antagonist being weaker than a full agonist and the fact that full kappa agonists are often dysphoric). Most world governments would love that--an effective painkill that made you feel like ass, a cure worse than the symptom.

 

[fastandbulbous]

I imagine that no-one has gone down that route because the OH group is a tertiary alcohol, and unless you use very carefully controlled conditions, esterification can have elimination as a side reaction to produce a 4-phenyltetrahydropyridine derivative (the same reaction, carried out without the utmost care and attention, was responsible for the side product in the synth of MPPP, namely MPTP)

Who wants to accidentally discover a new Parkinson's disease inducing drug?


Riemann Zeta
They have produced them; 5,9-dimethylbenzomorphans (eg phenazocine, metazocine and pentazocine). They're kappa agonists, partial mu agonists and have good analgesic properties. They also have a high incidence of psychotic episodes, hallucinations - generally causing people to scare the shit out of themselves and their loved ones. If the effects of salvinorin A are typical of all kappa agonists, you can see why a lot of people might have problems with them (to put it mildly)