2-(N-Cyclopropylamino)-3-chloropropiophenone

[dip12]

Anyone have access to this article? ...

J Med Chem. 2009 Nov 12;52(21):6768-81.
Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction.
Carroll FI, Blough BE, Abraham P, Mills AC, Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy KT, Navarro HA, Gatch MB, Forster MJ.
Source

Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA. [email protected]
Abstract

A series of bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [(3)H]dopamine ([(3)H]DA), [(3)H]serotonin ([(3)H]5HT), and [(3)H]norepinephrine ([(3)H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [(125)I]RTI-55 in cloned transporters. Several analogues showed increased [(3)H]DA uptake inhibition with reduced or little change in [(3)H]5HT and [(3)H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3-chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction.

PMID:
19821577

Wonder if they literally mean a dopamine agonist or instead it's overall pharmacology. Also wonder what that Cylopropyl group would do on other beta-ketones...

 

[Nagelfar]

Wonder if they literally mean a dopamine agonist

It says 'indirect agonist', which is the same class as cocaine (DRI) and amphetamine (DRA), not to be confused with direct agonism. Indirect agonists are not "agonists". They are releasers or reuptake inhibitors, etc.

 

[23536]

I find bupropion to be one of the most dysphoric drugs I know, and probably because of the noreprinephrinergic properties of it and its metabolites. A dopaminergic analogue with negligible action as an NRI would probably be interesting.

 

[Nagelfar]

A dopaminergic analogue with negligible action as an NRI would probably be interesting.

Dopamine metabolizes to norepinephrine, so perhaps a DRI that acts as an NE reuptake "enhancer" would be best. DA & NE are just so structurally similar, one might think it need be a combination of two chemicals to have such an effect.

 

[Hammilton]

a more readily accomplished goal would just be to block dopamine metabolism to NE!

 

[23536]

^the funny thing with that is, when cocaine-conditioned animals are given a dopamine beta hydroxylase inhibitor, they decrease their cocaine self-administration

https://etd.library.emory.edu/view/record/pid/emory:16nrf

is this because the experience is given wings, or does it turn sour?

 

[sekio]

I can agree with NeRI effects beign remarkably unpleasant. I remember once when I was young and impressionable I took (stupidly) an undisclosed quantity of Strattera... looking back on it now I realize that the pills were likely 100mg. (!) In short I felt like a train had hit me.

I think you need some NE activity to provide a good 'push' to a stimulant though. 'Pure' DRI's as described to me (or at least more selective for DA ones) are just compulsion inducers than anything else, I think.

 

[atrollappears]

I think that NE does a lot more than we give it credit for. Norepinephrine depletion in the mouse PFC completely blocks reward from amphetamine.
http://neuro.cjb.net/content/23/5/1879.short
Personally, I find sudafed a more effective study-stimulant than adderall or especially dexedrine.

 

[Nagelfar]

I think that NE does a lot more than we give it credit for. Norepinephrine depletion in the mouse PFC completely blocks reward from amphetamine.

Possibly a synergy of subtype affinity for pure 'euphoria' (or manners of euphoria, sexual stimulation versus focus & increase of novelty interest, etc.) could be found with just a select DA receptor & select NE receptor combination at the exclusion of other subtypes for either.

 

[sekio]

Norepinephrine depletion in the mouse PFC completely blocks reward from amphetamine.

This only further reinforces the theory that NE and DA are both needed to provide good 'classical stimulant' action.

 

[atrollappears]

Possibly a synergy of subtype affinity for pure 'euphoria' (or manners of euphoria, sexual stimulation versus focus & increase of novelty interest, etc.) could be found with just a select DA receptor & select NE receptor combination at the exclusion of other subtypes for either.

Possibly, although that's complicated by both DA and NE autoreceptors. For example, clonidine tends to kill my amph buzz, although it's an alpha 2 agonist and the postsynaptic alpha 2's seem to complement amph's properties IIRC (sorry, don't remember enough about that study to find and cite ). Interestingly, though, the sexual stimulation remains completely intact.

 

[Nagelfar]

This only further reinforces the theory that NE and DA are both needed to provide good 'classical stimulant' action.

SERT may have something to do with satiety as well (even as working against aspects of habituation). Though such satiety could be reinforcing in & of itself. I think of cocaine's extreme reinforcing properties as an SNDRI; most other SRIs lessen reinforcement, but there might be something said for a certain ratio of it.

 

[atrollappears]

SERT may have something to do with satiety as well (even as working against aspects of habituation). Though such satiety could be reinforcing in & of itself. I think of cocaine's extreme reinforcing properties as an SNDRI; most other SRIs lessen reinforcement, but there might be something said for a certain ratio of it.

Yeah cocaine doesn't just look like the sum of its parts, although I don't know how sigma agonism, Na blockage, and muscarinic whateveritdoes play into it. Getting a bit off-topic here, but I recall a study describing amphetamine-induced behaviors in mice that are selectively and only blocked by serotonin antagonists, implying that amphetamine causes serotonin release downstream. It might be interesting to see how that would play with a sufficient, acute dose of an SSRI, since their lack of acute effect is the result of decreased serotonin release from 5-HT1A autoreceptors. If this purported serotonin release by amph were to overcome that, we might see something interesting, even an explanation for (uncut) cocaine's relaxant/anxiolytic properties as compared to MPH (should that effect by amph carry over to reuptake inhibitors).

 

[Nagelfar]

Yeah cocaine doesn't just look like the sum of its parts, although I don't know how sigma agonism, Na blockage, and muscarinic whateveritdoes play into it. Getting a bit off-topic here

Very off topic. However I believe Na blockage has some mechanism by which is explained the extremely rapid entry and speed of onset of effects, as most derivatives without its anaesthetic effects are (seemingly) all much reduced in their onset time, sodium channels do relate to DAT in some manner I know I've read. Perhaps the sum of its parts really does contribute to it as such a major example.

 

[atrollappears]

Very off topic. However I believe Na blockage has some mechanism by which is explained the extremely rapid entry and speed of onset of effects, as most derivatives without its anaesthetic effects are (seemingly) all much reduced in their onset time, sodium channels do relate to DAT in some manner I know I've read. Perhaps the sum of its parts really does contribute to it as such a major example.

Interesting! Could it be as simple as Na blockage -> increased extracellular H2O -> increased fluid into which for cocaine to dissolve? Probably not, the body never lets it be that simple... Also, what cocaine analogues are you referring to? Do you have any information about their comparative solubilities?

 

[23536]

did anyone examine the relatively-mundane mepropion?

 

[Nagelfar]

Interesting! Could it be as simple as Na blockage -> increased extracellular H2O -> increased fluid into which for cocaine to dissolve?

Possibly, I hadn't thought of that possibility, which is a good one. Though I figured it to be something to do with Na channels assisting the proton swap in crossing different membranes to its active site. Possibly, due to affinity for channel docking, 'riding the sodium channels', as it were, into the brain.

If you just do a search for cocaine analogues, you'd be hard pressed to find one with even as fast of an onset as cocaine itself. I have been looking for one that is (clearly & undisputedly) superior in reinforcing onset myself for years, out of a pharmacological interest in cocaine itself, and without luck. It may be due to a bias of focus in research however.