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Pharmacology of bupropion (what does that chlorine do?)

dingophone

dingophone

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Title pretty much explains the question. I've been looking up to see any explanations about why the 3-chloro substituent is added, but I can't find anything. My speculation is that is makes the halflife longer (the tert-butyl group seems to be mostly responsible for blocking reuptake) but this is pure speculation. Can anyone enlighten me?
 
I'm pretty sure buproprion was made by synthesizing a bunch of analogues (2, 3, 4- chloro, 2, 3, 4 - methoxy, N-isopropyl, N-t-butyl, etc etc) and picking the one with the most favorable binding affinities & kinetics.

You're being too reductionist here. The reuptake inhibition properties comes from the fact it's a cathinone. The selectivity for is increased because of the t-butyl substituent (as it gets metabolically hydroxylated & turns to a cyclic NDRI called radafaxine aka 6-hydroxy-buproprion.

The t-butyl group on the nitrogen probably contributes more to the extended half life - but it also adjusts selectivity for the monoamine transporters, away from serotonin & dopamine. The chloro substitution helps tune selectivity even more. But both of these work in concert with the cathinone structure; you can't really generalise and say "the t-butyl group is responsible for blocking uptake" - because plain cathinone blocks transporters quite well!
 
sekio said:
I'm pretty sure buproprion was made by synthesizing a bunch of analogues (2, 3, 4- chloro, 2, 3, 4 - methoxy, N-isopropyl, N-t-butyl, etc etc) and picking the one with the most favorable binding affinities & kinetics.

You're being too reductionist here. The reuptake inhibition properties comes from the fact it's a cathinone. The selectivity for is increased because of the t-butyl substituent (as it gets metabolically hydroxylated & turns to a cyclic NDRI called radafaxine aka 6-hydroxy-buproprion.

The t-butyl group on the nitrogen probably contributes more to the extended half life - but it also adjusts selectivity for the monoamine transporters, away from serotonin & dopamine. The chloro substitution helps tune selectivity even more. But both of these work in concert with the cathinone structure; you can't really generalise and say "the t-butyl group is responsible for blocking uptake" - because plain cathinone blocks transporters quite well!
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Right, I was definitely being too reductionist. The cathinone structure certainly is the source of reuptake inhibition. However, you mention that the t-butyl group adjusts towards norepinephrine, but bupropion has significantly higher affinity for the dopamine transporter than the serotonin or norepinephrine transporters. Radafaxine, however, does have much higher affinity for the NE transporter (26% of bupropion DAT inhibition for bupropion, vs. 106% of bupropion DAT inhibition for radafaxine). I'm guessing the cyclic structure would contribute some to this?

The 3-Chloro substitution appears to be fairly uncommon, but based on the (extremely limited) analyses of 3-CMC and 3-FMC, you'd definitely be correct. Now, what would happen if you simply had 3-Chloro-N-t-butyl-cathinone? What would likely change?
 
The reuptake inhibition properties comes from the fact it's a cathinone.
Click to expand...

To some extent, but cathinone and methcathinone seem to function primarily as monoamine releasers. I believe that they exert stronger direct adrenergic agonism than their amphetamine analogues, and their beta-hydroxy metabolites are certainly quite adrenergic, leading to a 'feel' distinct from the parent compounds. It seems to me that one can instead generalize that given a cathinone skeleton, extension of the alkyl chain tends to push activity toward reuptake inhibition.

ebola
 
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