4-FA (or other amphetamine analog) daily for ADD

[Roger&Me]

since fluorine is significantly smaller than hydrogen, I doubt it's an issue.

The covalent radius of fluorine is roughly twice that of hydrogen.

 

[DoctorChemX]

The covalent radius of fluorine is roughly twice that of hydrogen.

LOL Yes!! Thats true Roger&Me, i was going to say that, and let's
not forget what we learnt in one of our first chemistry-classes, fluorine
is THE MOST REACTIVE element there is because it's also the most
ELECTRONEGATIVE which means it will react with almost any element.

 

[Roger&Me]

^Well, when fluorine is covalently bonded (as in 4-FA), its very unreactive. Especially when its covalently bonded to an aromatic system, because to detach it you would have to temporarily break the aromaticity which is very energetically unfavorable.

 

[ebola?]

To put it colloquially, the relevant reaction already happened.

 

[atrollappears]

Yes, but it is possible that excess serotonin present after SSRI's SERT blockade would compete with the agonist when both are trying to bind to serotonin receptors. For example, this is why amantadine, a dopamine agonist, might not work as well if a dopamine re-uptake inhibitor is co-administered with it.

Ah interesting, I didn't know that. But, correct me if I'm wrong, wouldn't that mean that the end result would be more net activation of serotonin receptors, even if the 4-FA is binding less? (My impression is that serotonin is a pretty active serotonin agonist )

LOL Yes!! Thats true Roger&Me, i was going to say that, and let's
not forget what we learnt in one of our first chemistry-classes, fluorine
is THE MOST REACTIVE element there is because it's also the most
ELECTRONEGATIVE which means it will react with almost any element.

Right well it's precisely because of that electronegativity that it's so small. But yeah, I forgot that the radius changes when it's bonded. I guess that explains why it has more affinity for SERT than amphetamine then, since the general SAR seems to be that increased size of para substituent -> increased SERT affinity.

 

[Amu]

Ah interesting, I didn't know that. But, correct me if I'm wrong, wouldn't that mean that the end result would be more net activation of serotonin receptors, even if the 4-FA is binding less? (My impression is that serotonin is a pretty active serotonin agonist )

Not necessarily, it is possible endogenous neurotransmitters and "exogenous" receptor agonists would react in an unpredictable way at receptor binding sites. Some people experience potentiation of amphetamine when NRI's like Wellbutrin/Desipramine/Strattera are co-administered whereas others experience partial or complete blocking of amphetamine's effects. MAOIs on paper should potentiate stimulants, but sometimes they don't have any effect, and sometimes they even interfere with stimulants, how should this be explained? Some studies have showed MAOIs increase DA levels, some have shown they don't, same applies for NE/SER.

Not related directly, but here's an interesting study:
http://www.ncbi.nlm.nih.gov/pubmed/12105119

The ternary complex model of G-protein-linkage to receptors holds that agonists increase the affinity of the receptors for the G protein. Consequently, an agonist can exert the greatest inhibition of the binding of radioligands which are also agonists. We hypothesized that competition from endogenous dopamine in striatum of living mice should thus have a greater effect on the binding of the D(2,3) agonist N-[(3)H]propylnorapomorphine ([(3)H]NPA), than on the binding of the D(2,3) antagonist [(11)C]raclopride in living brain. The binding potential (p(B(0))), defined as the ratio of bound-to-unbound ligand after reserpine treatment, was measured in mouse striatum for [(11)C]raclopride (p(B(0))(RAC)(C)) = 8.5, and for [(3)H]NPA(p(B(0))(NPA)) = 5.3. Relative to these baseline values after dopamine depletion, saline-treatment decreased the p(B) of [(3)H]NPA by one-half, while the p(B) of [(11)C]raclopride declined by only one-third. Amphetamine decreased the p(B) of [(3)H]NPA to a greater extent than that of [(11)C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [(3)H]NPA than for [(11)C]raclopride at its highest occupancies. Thus, the agonist binding was more sensitive than antagonist binding to competition from endogenous dopamine. Dopamine agonist ligands may be especially useful for PET studies of dopamine receptor occupancy by endogenous synaptic dopamine. Analysis of the effect of dopamine occupancy on the inhibition of agonist indicated a limited supply of G protein, with a maximum ternary complex fraction of 40% of maximum antagonist binding capacity.

I'm sure in most circumstances agonists + (re-uptake blockers / releasing agents) should produce more activation of receptors

 

[atrollappears]

Not necessarily, it is possible endogenous neurotransmitters and "exogenous" receptor agonists would react in an unpredictable way at receptor binding sites. Some people experience potentiation of amphetamine when NRI's like Wellbutrin/Desipramine/Strattera are co-administered whereas others experience partial or complete blocking of amphetamine's effects. MAOIs on paper should potentiate stimulants, but sometimes they don't have any effect, and sometimes they even interfere with stimulants, how should this be explained? Some studies have showed MAOIs increase DA levels, some have shown they don't, same applies for NE/SER.
...
I'm sure in most circumstances agonists + (re-uptake blockers / releasing agents) should produce more activation of receptors

Well I'd understand the unpredictable interaction between amphetamine and DA/NE reuptake inhibitors, since amphetamine is dependent on reuptake to induce release, but also acts as a reuptake inhibitor. It would probably depend which method of action is predominating.
The bit about MAOIs is definitely strange though. Maybe autoreceptor activation?