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Frakefamide - A novel tetrapeptide peripheral mu agonist

Hammilton

Hammilton

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In animal models frakefamide (FF) is a potent analgesic that acts as a peripheral active µ-selective receptor agonist. In this double-blind, randomized, double dummy four-way crossover study in 12 healthy male subjects, we investigated the effects on resting ventilation of FF and 2 dose levels of morphine compared with placebo. Each drug was infused for 6 h. The subjects received 1.22 mg/kg FF, 0.43 mg/kg morphine (M-large), and 0.11 mg/kg morphine (M-small). Sodium chloride 9 mg/mL was used as placebo. Ventilation was measured by pneumotachography and inline capnography. Blood was collected and plasma concentrations of FF and morphine and its metabolites were analyzed. Within 15 min after administration of FF all subjects complained of a transient myalgia, which disappeared within 30 min. At target measurement (335 min), there were no differences in tidal volume among the groups. Respiratory rates were, however, slower in the two M-groups (P < 0.05 in M-small and P < 0.001 in M-large) compared with FF and placebo. Minute volume was significantly less in the M-large group compared with the FF (P < 0.01) and placebo (P < 0.01) groups. This difference was reflected by an elevated ETco2 in the M-large group (P < 0.01). We conclude that, during resting ventilation, FF, unlike morphine, did not cause central respiratory depression. This suggests that FF has only peripheral µ-opioid agonist activity in humans.
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(full study available free)


SO! My big question is: how the hell does a peripheral mu agonist cause analgesia? I thought mu related analgesia was produced via central means. Obviously not the case, or at least not entirely the case.

Any thoughts?

Loperamide is largely devoid of analgesic effects in those of us with functional blood brain barriers. So what does this study teach us? I'm at a loss.
 
What's the bibliography?

Edit:
"A novel molecule (frakefamide) with peripheral opioid properties: the effects on resting ventilation compared with morphine and placebo."
Oesterlund Modalen, Asa; Quiding, Hans; Frey, Joana; Westman, Lars; Lindahl, Sten
Anesthesia & Analgesia 2005, 100(3), p.713
 
To facilitate discussion, the structure:

L-tyrosyl-D-alanyl-4-fluoro-L-phenylalanyl-L-Phenylalaninamide

Interesting! para-F-Phe and a D-amino acid.
 
Yeah, super interesting huh!

I mean to compare this structure to the thoughts the the guys who wrote that triamine opioid paper had (it was posted at bl, i think morphiquet requested it).
 
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