opioid antagonists that DON'T cross BBB

[daddysgone]

i was curious if there were any opioid antagonists that did NOT cross the blood brain barrier. if such a compound exists, i think it would prove quite useful. this would allow the desirable CNS effects of opioids to do their magic, while blocking the annoying (and painful) gastrointestinal effects. there are plenty of opioids out there dont cross the BBB but bond quite easily to GI receptors (loperamide). surely there must be antagonists that bond to GI receptors thus blocking the opioids and their GI effects, but do not cross the BBB, and thus have no effect on the CNS effects. any thoughts???

 

[mad_scientist]

http://en.wikipedia.org/wiki/Methylnaltrexone

http://en.wikipedia.org/wiki/Alvimopan

 

[Ham-milton]

very useful, just not very used yet.

 

[CH3CH2OH]

Might these inhibit pain relief by blocking (occupying) the peripheral opioid receptors? I do not know how much effect they have in pain relief from opioids, but I would imagine it could have some effect.

 

[MattPsy]

I'd like to see some novel ligands of this type derived from the N,N-dimethyl-4-arylalkyl-1-arylcyclohexanamine class because you should be able to produce easy(ier) to synthesize ones but with superhigh affinities so you can reverse overdose of the newer superpotent fentanyl analogues... seems to me that that N can be made quaternary easily enough (to make it peripheral only), then you need a structural feature to block agonist behavior...

 

[daddysgone]

http://en.wikipedia.org/wiki/Methylnaltrexone

http://en.wikipedia.org/wiki/Alvimopan

are either of these substances currently available- and if so would they require prescriptions. any other substances which would achieve the same effect which might be easier to obtain? thanks

 

[morphiquet]

there are µ-antagonists in coffee, the most potent being caffeoylquinide. it is periperally acting due to its high solubility in water (many hydroxys) plus i guess they wouldn't survive first-pass.
they all have affinities in the micromalar range, but if you would extract decaffeinated coffee and eat this in capsules you should gain good effects.

 

[Paregoric Kid]

I've been following the development of these drugs for a while. unfortunately alvimopan, which was going to be marketed under the tradename Entereg/Entrareg, suspended clinical trials. it seems unlikely it will ever come out and it was pretty far a long, I think phase II or III; it was in development for years. in fact if you google it you'll see glaxo and adolor had their stocks plummet after the news: http://seekingalpha.com/article/31845-glaxo-and-adolor-suspend-alvimopan-trial-adolor-shares-plummet

the good news is that wyeth and progenics are still developing methylnaltrexone and it should be on the market in a year or so.

and no if it works as they say it should then it would not cross the BBB and the CNS effects from opiates/opioids would not be effected. it would only effect things like constipation, which is its primary application.