[smart (OP)]

Naloxone availability is limited and can be used for emergency treatment of opioid overdose from fentanyl and heroin. I would like your input on designing a synthetic and functional opioid antagonist for medical purposes. The design of this medication could be of tremendous help for people struggling with opioid overdose. Can we use the power of the internet to gather collective knowledge on the synthesis of novel opioid receptor antagonists?

What do you think?

[chiralSPO]

Naloxone availability is only limited by policy. It is neither terribly expensive to manufacture nor particularly hard to transport/store/distribute. In the US (I can only speak about the US, because that's where I am), it is a scheduled drug and requires a prescription. However, there is a push to remove this barrier, and allow it to be sold over the counter or included in standard first aid kits (opiate overdoses now supposedly kill more Americans per year than gun violence and car crashes combined!)

would like your input on designing a synthetic and functional opioid antagonist for medical purposes. The design of this medication could be of tremendous help for people struggling with opioid overdose. Can we use the power of the internet to gather collective knowledge on the synthesis of novel opioid receptor antagonists?

This is probably not a very effective mode of drug discovery. Even assuming you are able to bring together hundreds of the most knowledgeable and creative minds in the world, you will never successfully discover a new drug by thought experiment alone.

Actual experimentation is required to find structures that bind to the desired targets, and then iterative experimentation to improve binding, bioavailability, and clearance, as well as limiting toxicity and side effects. You also have to figure out how to make and distribute these compounds in an economically feasible way on scale. Pharmaceutical companies typically spend more than $1,000,000,000 on research for each new drug that comes to market, and the whole process takes at least a decade from conception to prescription.

[Bored chemist]

Naloxone availability is limited

It doesn't seem very limited to me.
https://en.wikipedia.org/wiki/Naloxone#Legal_status

And it's not difficult- or expensive to make.
"Its wholesale price in the developing world is between US$0.50 and 5.30 per dose."
(from the same page)

[chris]

Returning to the original question, naloxone is already a synthetic anti-opioid, so why would we want to design another one? And there is actually another opioid receptor blocker called naltrexone, which works the same way and has the same indications.

[Bored chemist]

Strictly speaking they are both semi-synthetic opioid antagonists.
They are made (indirectly) from opium poppies.

[smart (OP)]

Returning to the original question, naloxone is already a synthetic anti-opioid, so why would we want to design another one?

Naloxone has several noteworthy limitations:
- Shorter half-life than heroin
- Side-effects including seizure and arrhythmia
- Restricted availability to medical professionals or as a prescription drug for heroin addicts

See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661437/

Note also that the patent for Naloxone is expired. This mean we could design a updated version of Naloxone to address theses limitations in pill form. 

[evan_au]

the patent for Naloxone is expired. This mean we could design a updated version of Naloxone to address theses limitations in pill form.

1. If someone had the ability to improve on Nalaxone by modifying the chemical structure to make a version of it that could be taken in pill form (eg equally effective, more portable, longer lasting, cheaper to manufacture, etc), then that could have been done while it was still under patent. You then make some cross-licensing arrangement with the owner of the current patent. The purpose of patents is to accelerate innovation by publishing the details of an invention, so that others can make improved versions of it (and patent those improvements).

2. The patent has now expired, so anyone can make use of the published patent to produce Nalaxone, which often makes it cheaper and more readily available (subject to legal constraints, of course). The purpose of patent protection is to give the inventor time to make some money on their invention, before the patent expires and anyone can make it without license fees.

But Nalaxone is a drug that is administered to people who are suffering a heroin overdose - they may be agitated, vomiting, or unconscious, and at risk of death within minutes.
- Pills take many minutes to digest, and may never reach the stomach if the patient is vomiting.
- Getting someone to take a pill with a glass of water might be difficult if they are agitated, dangerous if they are vomiting, and impossible if they are unconscious
- A glass of water is even less portable than a single-use syringe
- The intravenous injection can be effective in as little as 2 minutes.

But Nalaxone is sometimes combined with opioids in a single pill to reduce the impact of  misuse.
See: https://en.wikipedia.org/wiki/Naloxone

[Bored chemist]

- Side-effects including seizure and arrhythmia
- Restricted availability to medical professionals or as a prescription drug for heroin addicts

"Restricted availability to medical professionals or as a prescription drug for heroin addicts"
Did you read the bit from WIKI which I cited, or the paper you cited yourself?

The difficulty with obtaining it is solely due to dimwitted legal restrictions which are over-ruled in many states ( there's list on WIKI) and could be removed immediately if Trump was really concerned about the opiate explosion.

Having a new drug wouldn't help.
What they need is a readily available drug.
Before a drug is made easy to get , it has to be shown to be safe. Naloxone has 30 or 40 years of evidence of that.
A new drug wouldn't.

I suspect that any drug that blocks the opiate receptors risks producing seizures but I'd need to check the pharmacology.
Fundamentally,  and drug will have side effects and in overdose anything (drug or not) is going to have toxic effects. An ew drug wouldn't solve that problem.

Incidentally, legalisation would solve most of the problems raised here.
it would ensure better quality control- thereby reducing the incidence of overdose- and it would remove the issues (detailed in the paper you cited) which delay contacting the emergency services when someone witnesses an overdose reaction.

[exothermic]

the opiate explosion
Having a new drug wouldn't help.
What they need is a readily available drug.

We really need to just forget about the opioid "crisis" altogether.

Much like the foolish "War on Drugs" fallacy.... there is no end.

Naloxone availability just pushes the users to take larger doses..... because they know the Narcan is there to revive them.

I've seen this first-hand, so I know it's a reality.

~

[exothermic]

We really need to just forget about the opioid "crisis" altogether.

Much like the foolish "War on Drugs" fallacy.... there is no end.

Naloxone availability just pushes the users to take larger doses..... because they know the Narcan is there to revive them.

I've seen this first-hand, so I know it's a reality.

People intentionally OD to be revived at 'Narcan parties'... Emergency responders express frustration
Posted: Aug 04, 2017 08:38 AM MDT

http://www.nbcmontana.com/news/irresistible/people-intentionally-od-to-be-revived-at-narcan-parties/599532613


~

[exothermic]

Naloxone Party Balloons:

[exothermic]

We really need to just forget about the opioid "crisis" altogether.

Much like the foolish "War on Drugs" fallacy.... there is no end.

Naloxone availability just pushes the users to take larger doses..... because they know the Narcan is there to revive them.

I've seen this first-hand, so I know it's a reality.

People intentionally OD to be revived at 'Narcan parties'... Emergency responders express frustration
Posted: Aug 04, 2017 08:38 AM MDT

http://www.nbcmontana.com/news/irresistible/people-intentionally-od-to-be-revived-at-narcan-parties/599532613

'NARCAN PARTIES:' Drug users overdosing to be brought back to life

http://www.wsoctv.com/news/local/narcan-parties-drug-users-overdosing-to-be-brought-back-to-life/580740050


~

[smart (OP)]

The transdermal delivery of naloxone is a promising possibility. I wonder why emergency responders could not use this to avoid heroin/fentanyl rebound: "Upon single dose administration, the steady-state levels were maintained from 4-48 h, which proves the clear advantage of transdermal delivery system over the current mode of administration, i.e., intravenous (i.v.) bolus which is effective upto a maximum of 1.5h."

See: https://www.ncbi.nlm.nih.gov/pubmed/15778059

[exothermic]