Chemistry of opiates

[sekio]

Difenoxin has a carboxylic acid moiety. It's normally charged so it greatly impedes BBB penetration - but not entirely (like with loperamide). It is indeed a weak analgesic like you predict. Apparently it is a sch.IV (DEA) product when combined with atropine for diarrhea.

Diphenoxylate is the ethyl ester of difenoxin. It too is used as an anti-diarrheal agent in combination with atropine.

 

[Ulcer]

Difenoxin has a carboxylic acid moiety. It's normally charged so it greatly impedes BBB penetration - but not entirely (like with loperamide). It is indeed a weak analgesic like you predict. Apparently it is a sch.IV (DEA) product when combined with atropine for diarrhea.

Diphenoxylate is the ethyl ester of difenoxin. It too is used as an anti-diarrheal agent in combination with atropine.

That seems to fit my observations nicely I think.

I've tried to dig around for some studies into difenoxin/difenoxylate, but I can't seem to find any solid evidence regarding either drugs specific opioid action outside some vague mu/delta references. I suppose that suggests that the drugs are non-selective opioid agonists, but I'd like to be more certain.

I'd also like to attach some numbers to the structures to see if theres a clear trend regarding how a carboxylate anion affects the potency of the drugs i.e. if difenoxin had low potency and difenoxylate had higher potency, it would fit the observations perfectly.

Thanks for that by the way, some really interesting reading here.

Side note: Is it just me or are difenoxin and difenoxylate named in reverse? I would think the carboxylate would have the 'oxylate' suffix.

 

[Hyperthesis]

Side note: Is it just me or are difenoxin and difenoxylate named in reverse? I would think the carboxylate would have the 'oxylate' suffix.

Nope, it's just you
In the nomenclature of organic molecules, one way to name an ester is to treat him like being made from ionic components, ie. as a salt. Hence, the acid-part would be named with an -ate-suffix, indicating a (theoretical) anionic nature, and the ethyl-part would according being treated as an cation. From this logic were names derived like "ethyl acetate", or in this case "XY diphenoxylate". The difenoxin-molecule on the other hand has a protonated carboxylic acid moeity and isn't named with an -ate-suffix

 

[Ulcer]

Nope, it's just you
In the nomenclature of organic molecules, one way to name an ester is to treat him like being made from ionic components, ie. as a salt. Hence, the acid-part would be named with an -ate-suffix, indicating a (theoretical) anionic nature, and the ethyl-part would according being treated as an cation. From this logic were names derived like "ethyl acetate", or in this case "XY diphenoxylate". The difenoxin-molecule on the other hand has a protonated carboxylic acid moeity and isn't named with an -ate-suffix

Fair enough. The "yl-ate" nomenclature of esters never occured to me.

Regarding the opioid activity of the compounds, can anybody find any metric values?

The only hint I can find regarding the compounds is that difenoxin as a carboxylate is regarded as an anti-diarrhoeal with opioid agonist properties and difenoxylate as an ester is regarded as an opioid agonist with anti-diarrhoeal properties.

Which either means that the anti-diarrhoeal properties are stronger and the opioid activity is unchanged when there is a carboxylic acid moiety or the opioid activity is stronger and the anti-diarrhoeal properties are unchanged when there is a carboxylic acid moiety.

I feel like this mystery can be solved if we can find an answer to that question.

 

[sekio]

Anti-diarrhoeal properties = perhipheral opioid agonism
Opioid agonism = central opioid agonism

This matches up really well with the charged carboxylate being effective as a perhipheral agent because it does not cross BBB, whereas the ester prefers to cross BBB (relative to the carboxylate) due to the decreased ionisation.

 

[Hyperthesis]

There are affinity values for Difenoxin-HCl in the literature, albeit from the days when people didn't seem to know yet the difference between the receptor subtypes. The displacement-assay was performed with a certain fraction from brains of male Sprague-Dawley rats. The hot ligand was 3H-naltrexone. Analgesic potency was determined by the tail withdrawal reflex (TWR). Anti-diarrheal potency was determined by the castor oil test (COT).

Difenoxine-HCl:
IC50: 18 nM (in 0.05 M Tris-buffer, pH 7.4)
IC50: 60 nM (in 0.05 M Tris-buffer + 0.1 M NaCl)
ED50(TWR): - (=no central activity)
COT(1 h): 0.087 µmol/kg
for comparison: the COT-value of loperamide was 0.29 µmol/kg

Difenoxylate-HCl:
IC50: 140 nM (in 0.05 M Tris-buffer, pH 7.4)
IC50: 1200 nM (in 0.05 M Tris-buffer + 0.1 M NaCl)
ED50(TWR): - (=no central activity)
COT(1 h): 0.31 µmol/kg
for comparison: the COT-value of loperamide was 0.29 µmol/kg

Reference: Arzneimittelforschung 1976, 26: 1548
TWR-assay: Arzneimittelforschung 1963, 13: 502
COT-assay: Arzneimittelforschung 1972, 22: 516