Rapid Onset DRI's?

[Sphinx (Afterlife)]

Has anyone come across any DRI's with the following qualities;

- Very rapid onset
- Short duration, 15-30 minutes
- Highly selective for only DR inhibition, not sero or nor
- High potency, something putting it in the 10mg or lower range for a 100kg individual and majority DT occupancy
- Preferably not a cocaine analog, but if thats all you know then spill em


(±)-threo-3,4-dichloromethylphenidate (3,4CTMP) seems pretty close but I cant find anything on its duration or its speed of onset, and not even sure what methylphenidate itself's onset and duration looks like. Maybe somone here knows the methylphen SARs and can take a stab?

 

[hussness]

Onset will depend on route of administration as long as the drug isn't a prodrug. What exactly do you mean by a cocaine analog? Methylphenidate could be considered a cocaine analog by certain definitions. I think methylphenidate has a half life of around 6-8 hours, and I'm pretty sure the dichloro analog you mentioned probably has a similar half life. Something with that short of a half-life would something that could easily be removed by an enzyme with metabolites that aren't active. What is the problem with cocaine analogs anyway?

 

[Sphinx (Afterlife)]

What is the problem with cocaine analogs anyway?

Nothing if they dont 'look' similar to cocaine. But if its just a lil switch here or a lil switch there thats unacceptable.

But arent most the cocaine analogs like the WINs longer acting than cocaine?? And arent they more SNDRI rather than just DRI's?

 

[Smyth]

Maybe the 4-fluoro analog of focalin? I think any such postulations of a dichloro analog are not justified for ritalin, and this idea is plain greedy.

 

[Sphinx (Afterlife)]

then theres...

Synthesis and biological evaluation of 1-[1-(2-benzothienyl)cyclohexyl]piperidine homologues at dopamine-uptake and phencyclidine- and sigma-binding sites.
He XS, Raymon LP, Mattson MV, Eldefrawi ME, de Costa BR.

Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Piperidine and cyclohexyl ring homologues of the high-affinity dopamine (DA) uptake inhibitor 1-[1-(2-benzothienyl)cyclohexyl]piperidine (BTCP, 3) were each prepared in four steps from the appropriate cycloalkanones. These compounds were tested for their ability to displace [3H]BTCP and [3H]cocaine and to inhibit [3H]DA uptake in rat striatal homogenates. The ratios IC50([3H]cocaine)/IC50([3H]BTCP) ranged from 62 for BTCP to 1.5 for 1-[2-(benzothienyl)-cyclopentylamine (17); cocaine gave a ratio of 0.6. This indicates that BTCP is the most selective of all the compounds tested for sites labeled by [3H]BTCP whereas cocaine is most selective for sites labeled by [3H]cocaine. The wide differences in the relative abilities of these compounds to displace [3H]BTCP and [3H]cocaine suggests that these two radioligands are labeling different sites on the transporter. In general, the compounds structurally related to BTCP exhibited greater selectivity for sites labeled by [3H]BTCP. However, several of the BTCP-related derivatives showed greater (compared with BTCP and cocaine) ability to displace [3H]cocaine. Most notably, 1-[1-(2-benzothienyl)cyclohexyl]pyrrolidine (7) exhibited a 3.4-fold greater affinity for these sites compared with BTCP and a 9-fold greater affinity at these sites than cocaine. Most of the BTCP homologues displayed greater ability to inhibit [3H]DA uptake in rat forebrain synaptosomes than cocaine. BTCP and 7 were the most potent of all the compounds tested in terms of their ability to inhibit uptake of [3H]DA. IC50 ratios for [3H]cocaine binding/[3H]DA uptake ranged from 0.47 for 1-[1-(2-benzothienyl)cyclopentyl]homopiperidine (11) to 8.8 for 1-(2-benzothienyl)cyclohexylamine (4). The importance of this ratio remains unclear in terms of identification of potential cocaine antagonists. As for BTCP, all of the compounds tested showed Ki values > 10,000 nM for displacement of [3H]TCP from rat brain homogenates. These compounds were able to displace the highly selective sigma receptor probe [3H]-(+)-pentazocine from guinea pig brain homogenates with Ki values ranging from 125 to 9170 nM. The significance of their sigma-binding activity in light of their dopaminergic properties is unclear. The diverse binding properties of these compounds at the DA-uptake site and their spectrum of inhibitory activities for [3H]DA uptake identifies them as a useful base for the development of subtype selective probes at this site. These compounds will allow further study of the structure and function of the "cocaine" receptor as well as the development of potential cocaine antagonists.


Anyone have access to the full article?

Or for that matter,

French ED, Lopez M, Peper S, Kamenka JM, Roberts DCS (1995): A comparison of the reinforcing efficacy of PCP, the PCP derivatives TCP and BTCP, and cocaine using a progressive ratio schedule in the rat. Behav Pharmacol 6:223-228

Chaudieu I, Vignon J, Chicheportiche M, Kamenka JM, Trouiller G, Chicheportiche R (1989): Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs. Pharmacol Biochem Behav 32:699-705


This may be more suitable... if I read correctly elsewhere, BTCP is sumthing like double the potency of cocaine which would put it somewhere between 50-100mg for a 100kg individual or so... no clue on its duration though.

 

[Smyth]

Yeah me have dat article.

 

[hussness]

Nothing if they dont 'look' similar to cocaine. But if its just a lil switch here or a lil switch there thats unacceptable.

But arent most the cocaine analogs like the WINs longer acting than cocaine?? And arent they more SNDRI rather than just DRI's?

I assume you are referencing the Analogs Act. I don't have any legal background, but even if there is little to no similarity chemically, the behavioural effects would probably be enough to put you on some pretty sticky legal ground.

 

[fastandbulbous]

If you want something that's a dopamine reuptake inhibitor with a fairly fat onset and an average human dose below 10mg (lasts hours rather than mins though), then 3,4-methylenedioxypyrovalerone (MDPV) fits the bill admirably. There's a thread simewhere in ADD about it

 

[nanobrain]

^Valera surely did DAT, too bad so sad,
he's gone, gone, gone
aint nothin gonna bring him back ;-)

 

[blase deviant]

That reminds me, I know long term use of a substance caused you to make more receptors, but does it also affect say DAT or SERT or whatever neurotransmitter it happened to have profound effects at?

(I'm curious mostly about long-term SSRI use, but also about substances in general... BTW, am I correct in that there isn't any GABA-transporter, or if so, benzos don't affect, just the amount of GABA receptors?)

 

[fastandbulbous]

Benzos are modulators of the GABA receptor - altering the size of the ion channel & therefore passage of chloride ions

 

[BilZ0r]

There are GABA transporters... 3 of them if my memory serves GAT-1 GAT-2 & GAT-3.

I don't think we know how benzos work exactly... I suspect it might differ from receptor subtype to receptor subtype... but on the whole, you can think that benzos act by increasing the affinity of GABA-A receptors for GABA... i.e. it doesn't effect the time course of the GABA mediated inhibitory event or it's maximum. (but that's not exclusively true).

 

[hussness]

If you want something that's a dopamine reuptake inhibitor with a fairly fat onset and an average human dose below 10mg (lasts hours rather than mins though), then 3,4-methylenedioxypyrovalerone (MDPV) fits the bill admirably. There's a thread simewhere in ADD about it

Has there been any update on the warning I read towards the end of all those posts about the metabolites being neurotoxic?

 

[dehmmy]

Onset will depend on route of administration as long as the drug isn't a prodrug. What exactly do you mean by a cocaine analog? Methylphenidate could be considered a cocaine analog by certain definitions. I think methylphenidate has a half life of around 6-8 hours, and I'm pretty sure the dichloro analog you mentioned probably has a similar half life. Something with that short of a half-life would something that could easily be removed by an enzyme with metabolites that aren't active. What is the problem with cocaine analogs anyway?

half life of dl-MPH (Ritalin.. methylphenidate) is more closer to 3-4 hours give or take an hour. Other variables obviously factor in.

In a publication by Dr. Nora Volkow, director of nuclear medicine at the Brookhaven National Laboratory in Upton, N.Y., says "We've given it [Ritalin] to cocaine users, and they say it's almost indistinguishable [when taken IV],'' Volkow says. The only significant difference was that Ritalin took over four times as long - 90 minutes - to leave the body." .. compared to cocaine's 20 min.