Methylphenidate has known abuse potential, particularily if snorted or injected, it is interesting to look at some of the analogues of methylphenidate as potential future stimulants or DOA's, because they have rather been overlooked on this and other forums, especially as they are very easily made.
methylphenidate is a pretty potent DAT NET inhibitor. strange really as it gets into the brain as fast as cocaine, yet is not really euphoric or particularly addictive, which kind of blows the speed of onset theory out of the water.
Some time ago on this forum there was some discussion of 2-benzyl pyridine as an analogue of desoxypipradrol. Another way of looking at this is 2 benzyl piperidine is a methylphenidate minus the carboxylic acid methyl ester.
the 4-chloro phenyl (2-(4-chlorophenylmethyl)piperidine- (chloro on the phenyl part of the benzyl bit) analog and the 3,4 dichlorophenylmethyl- are even more potent
the following are stolen from the paper below and are in order Ki RT55 displacement (so one sort of DAT affinity) nM, DA uptake IC50 nM, NE uptake IC50 nM.
Methiphenidate : 110, 79, 61 nM
Cocaine : 500, 240, 210 (5HT uptake 250) nM
4-chloromethiphenidate: 25, 11, 11 nM
3,4 Dichloromethiphenidate: 1.4, 23, 14 nM
the 3,4 is very potent indeed and what is interesting is the 3,4 dichloro compared to the 4-chloro has much higher DAT affinity, indicated by its very low Ki for RTI55 displacement but it isn't much more effective at inhibiting dopamine uptake, so this indicates that the 3,4 dichloro substitution is good for binding to DAT interfering with the site as RTI 55 (a phenyltropane) uses but that binding in this site does not necessarily cause efficient dopamine uptake blocking. perhaps there are several sites on DAT one of which is better at binding RTI 55 and another which is better at binding Dopamine.
the paper and patent below decsribe replacing the methoxycarbonyl with alkyl groups the most potent being isobutyl which when combined with a 4-chloro gives a compound with an IC50 DA uptake of 5.5 nM 14 times more potent than methiphenidate it is also rather DA selective IC50 NE is 9nM so 2:1 DA over NE. But this compound is slow to get into the brain and long lasting, I also doubt it will be any good for adhd because it has more DA than NE activity and the better ADHD drugs seem to have significant NE activity.
so what does ths mean?
well the substances above still have the methoxycarbonyl so are analogues of methiphenidate, removing this ester group gives 2-benzyl piperidine.
and...
I bet that 2 (4-chloro benzyl) piperidine is active at 5 mg or lower
I bet that 3,4-dichlorobenzyl piperidine is more potent. and that both isomers are active.
I would also bet that 4'4' dichloro desoxypiprardol is active at sub milligram doses.
the 2-(alpha methyl benzyl) piperidine is unknown but the 4 chloro version is described in this paper, and I would expect it to be less potent than methiphenidate and 2-benzyl piperidine.
lenghtenng the alpha methyl to an alpha propyl (alpha propyl benzyl) piperidine should be about 2 times more potent than 2-benzylpyridine. and very long lasting
I think we'll will have to wait a decade or so to find out...
patent, covers the same material as the article above but is free..
http://www.freepatentsonline.com/20060100243.html
methylphenidate is a pretty potent DAT NET inhibitor. strange really as it gets into the brain as fast as cocaine, yet is not really euphoric or particularly addictive, which kind of blows the speed of onset theory out of the water.
Some time ago on this forum there was some discussion of 2-benzyl pyridine as an analogue of desoxypipradrol. Another way of looking at this is 2 benzyl piperidine is a methylphenidate minus the carboxylic acid methyl ester.
the 4-chloro phenyl (2-(4-chlorophenylmethyl)piperidine- (chloro on the phenyl part of the benzyl bit) analog and the 3,4 dichlorophenylmethyl- are even more potent
the following are stolen from the paper below and are in order Ki RT55 displacement (so one sort of DAT affinity) nM, DA uptake IC50 nM, NE uptake IC50 nM.
Methiphenidate : 110, 79, 61 nM
Cocaine : 500, 240, 210 (5HT uptake 250) nM
4-chloromethiphenidate: 25, 11, 11 nM
3,4 Dichloromethiphenidate: 1.4, 23, 14 nM
the 3,4 is very potent indeed and what is interesting is the 3,4 dichloro compared to the 4-chloro has much higher DAT affinity, indicated by its very low Ki for RTI55 displacement but it isn't much more effective at inhibiting dopamine uptake, so this indicates that the 3,4 dichloro substitution is good for binding to DAT interfering with the site as RTI 55 (a phenyltropane) uses but that binding in this site does not necessarily cause efficient dopamine uptake blocking. perhaps there are several sites on DAT one of which is better at binding RTI 55 and another which is better at binding Dopamine.
the paper and patent below decsribe replacing the methoxycarbonyl with alkyl groups the most potent being isobutyl which when combined with a 4-chloro gives a compound with an IC50 DA uptake of 5.5 nM 14 times more potent than methiphenidate it is also rather DA selective IC50 NE is 9nM so 2:1 DA over NE. But this compound is slow to get into the brain and long lasting, I also doubt it will be any good for adhd because it has more DA than NE activity and the better ADHD drugs seem to have significant NE activity.
so what does ths mean?
well the substances above still have the methoxycarbonyl so are analogues of methiphenidate, removing this ester group gives 2-benzyl piperidine.
and...
I bet that 2 (4-chloro benzyl) piperidine is active at 5 mg or lower
I bet that 3,4-dichlorobenzyl piperidine is more potent. and that both isomers are active.
I would also bet that 4'4' dichloro desoxypiprardol is active at sub milligram doses.
the 2-(alpha methyl benzyl) piperidine is unknown but the 4 chloro version is described in this paper, and I would expect it to be less potent than methiphenidate and 2-benzyl piperidine.
lenghtenng the alpha methyl to an alpha propyl (alpha propyl benzyl) piperidine should be about 2 times more potent than 2-benzylpyridine. and very long lasting
I think we'll will have to wait a decade or so to find out...
J. Med. Chem., 50 (2), 219 -232, 2007. 10.1021/jm0608614
Slow-Onset, Long-Duration, Alkyl Analogues of Methylphenidate with Enhanced Selectivity for the Dopamine Transporter
Mark Froimowitz,*
Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.
patent, covers the same material as the article above but is free..
http://www.freepatentsonline.com/20060100243.html