User:Nuklear/Phenidate
ADHD is the most frequently diagnosed childhood neurobehavioral health problem and ±TMP is the drug most widely prescribed for its treatment. This piperidine-based stimulant affects sympathetic nervous system similar to pseudoephedrine, but stronger.
TMP Analogs
(Mark Froimowitz, et al. 2007)[1]
Methylphenidate was first synthesized 60 years ago, and is still commonly prescribed to ADHD sufferers. The activity of the compound, whose primary pharmacological action is catecholaminergic, resides almost entirely in the threo isomer. The active configuration of the active (+)-enantiomer has been determined to be RR from chemical conversion to compounds with known configuration, and this has been confirmed more recently by X-ray crystallography.
In cases where the 3D structure of the binding site in a target protein is not well defined, as is the case for the MATs, one can perform ligand-based design to develop a pharmacophore. That is, by studying the conformational properties of a series of pharmacologically similar compounds, one can form hypotheses regarding the pharmacophore. To that end, conformational analyses were performed on a series of DAT blockers, including cocaine and CFT. The preferred conformation of the tropane DA reuptake blockers was found to have an intramolecular H-bond between the carbonyl oxygen and the axial ammonium hydrogen. On this basis, a pharmacophore model was proposed in which the key feature was the orientation of the ammonium hydrogen. The model could explain why some DARIs, such as 1-amino-4-phenyltetralins and 3-phenyl-1-aminoindanes, have optimal activity as 2° amines whereas others, such as cocaine, have optimal activity as 3° amines. That is, an N-substituent in the 3° amine of the former is in the position required for the ammonium hydrogen. This pharmacophore model has been tested by the synthesis of rigid analogs of cocaine with defined orientation of the ammonium hydrogen, and different transporter selectivities were demonstrated that were consistent with its predictions.
More recently, the pharmacophore model was extended to methylphenidate by a conformational analysis of the threo and erythro isomers using the molecular mechanics program MM2-87, and the preferred conformer of the threo isomer was found to have an intramolecular H-bond between the carbonyl oxygen and the equatorial R3NH. Similar conformations were observed in a number of crystal structures of methylphenidate analogs with different phenyl substituents. This model also correctly predicted a decrease in activity when the 2° amines of methylphenidate analogs were N-methylated. Using these preferred conformers of methylphenidate and CFT, the compounds were superimposed and an essentially perfect fit was found for the sequence of atoms from the amine atom through the ester group. This suggests that TMP and CFT should share similar SARs w.r.t. the carbomethoxy side chain. On this basis the alkyl side-chain TMP analogs were prepared in order to test the hypothesis that intelligent SAR-based design can be successfully utilized to generate novel designer drugs. This is to say that the pharmacophoric elements are readily interchangeable, and not just hard-wired to a particular molecule (Meltzer, et al. 2006). Particularly, refering to the alkyl side-chains in the context of the pyrovalerone analogs recently reported. These are also useful catecholamine reuptake inhibitors. Like TMP, bioactivity is enantiospecific, although these can undergo racemization to a limited extent, through epimerization. The carbonyl can be reduced, via standard Clemmenson conditions, which has been done, and not just theory.
One less desirable aspect to the clinical use of TMP is that it typically must be administered 2-3 xs / day,[2] since the ester group is rapidly hydrolyzed or metabolized to produce the inactive acid.[3] TMP is a potent DARI but also has 'abuse potential'. There is evidence that the abusability of a drug is correlated with a fast onset and a short duration of action (Woolverton and Z.Wang, 2004).[4]
| Identification Marker | DAT IC50, nM (Ki, nM) | NET IC50, nM (Ki, nM) | SERT IC50, nM (Ki, nM) | IC50 and (Ki) Ratios | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | X | [3H]Dopamine | D.R. | [3H]Noradrenaline | D.R. | [3H]Serotonin | D.R. | NE ÷ DA | SER ÷ NE | |
| Cocaine | — | 240 ± 15 (500 ± 65) | 0.48 | 210 ± 30 (500 ± 90) | 0.42 | 250 ± 40 (340 ± 40) | .7353 | 0.875 (1) | 1.190 (0.68) | |
| MeOC=O | H | 79 ± 16 (110 ± 9) | .7182 | 61 ± 14 (660 ± 50) | .0924 | 51K ± 7K (65K ± 4K) | .7846 | .7722 (6) | 836.1 (98.48) | |
| O=COMe | p-Cl | 11 ± 2 (25 ± 8) | 0.44 | 11 ± 3 (110 ± 40) | 0.1 | 6K ± 1h (>9.8K) | 1.633 | 1 (4.4) | 890.9 (54.55) | |
| methyl | p-Cl | 22 ± 7 (180 ± 70) | .1222 | 35 ± 13 (360 ± 140) | .9722 | 1.9K ± 3h (4.9K ± 5h) | .3878 | 1.591 (2) | 54.29 (13.61) | |
| ethyl | p-Cl | 23 ± 5 (37 ± 10) | .6216 | 210 ± 30 (360 ± 60) | .5833 | 2.4K ± 4h (7.8K ± 8h) | .3077 | 9.130 (9.730) | 11.43 (21.67) | |
| 1-propyl | p-Cl | 7.4 ± 0.4 (11 ± 3) | .6727 | 50 ± 15 (200 ± 80) | 0.25 | 2.9K ± 11h (2.7K ± 6h) | 1.074 | 6.757 (18.18) | 58 (13.5) | |
| isopropyl | p-Cl | 32 ± 6 (46 ± 16) | .6957 | 51 ± 20 (810 ± 170) | .0630 | 3.3K ± 4h (5.3K ± 13h) | .6226 | 1.594 (17.61) | 64.71 (6.54) | |
| 1-butyl | p-Cl | 8.2 ± 2.1 (7.8 ± 1.1) | 1.051 | 26 ± 7 (230 ± 30) | .1130 | 4K ± 4h (4.3K ± 4h) | .9302 | 3.171 (29.49) | 153.8 (18.70) | |
| 3-isobutyl | p-Cl | 8.6 ± 2.9 (16 ± 4) | .5375 | 120 ± 40 (840 ± 130) | .1429 | 490 ± 80 (5.9K ± 9h) | .0831 | 13.95 (52.5) | 4.083 (7.024) | |
| 1-pentyl | p-Cl | 45 ± 14 (23 ± 7) | 1.957 | 49 ± 16 (160 ± 40) | .3063 | 1.5K ± 3h (2.2K ± 1h) | .6818 | 1.089 (6.957) | 30.61 (13.75) | |
| 4-isopentyl | p-Cl | 14 ± 2 (3.6 ± 1.2) | 3.889 | 210 ± 40 (830 ± 110) | .2530 | 7.3K ± 14h (5K ± 470) | .1137 | 15 (230.6) | 34.76 (6.024) | |
| 3-pentyl | p-Cl | 240 ± 60 (400 ± 80) | 0.6 | 330 ± 80 (970 ± 290) | .3402 | >9.4K (3.9K ± 3h) | 2.410 | 1.375 (2.425) | 28.48 (4.021) | |
| c-pentyl | p-Cl | 27 ± 8.3 (36 ± 10) | 0.75 | 44 ± 18 (380 ± 120) | .1158 | 4.6K ± 8h (5.7K ± 11h) | .8070 | 1.630 (10.56) | 104.5 (15) | |
| neopentyl | p-Cl | 60 ± 2 (120 ± 40) | 0.5 | 520 ± 110 (140 ± 400) | .3714 | >8.3K (3.9K ± 5h) | 2.128 | 8.667 (11.67) | 15.96 (7.5) | |
| c-pentymethyl | p-Cl | 21 ± 1 (9.4 ± 1.5) | 2.234 | 310 ± 40 (1.7K ± 310) | .1824 | 2.1K ± 9h (2.9K ± 80) | .8095 | 14.76 (180.9) | 6.774 (1.706) | |
| c-hexymethyl | p-Cl | 230 ± 70 (130 ± 40) | 1.769 | 940 ± 140 (4.2K ± 2h) | .2238 | 1K ± 2h (900 ± 400) | 1.111 | 4.087 (32.31) | 1.064 (.2143) | |
| benzyl | p-Cl | 370 ± 90 (440 ± 110) | .8409 | 2.9K ± 6h (2.9K ± 8h) | 1 | 1.1K ± 2h (1.1K ± 2h) | 1 | 7.838 (6.591) | .3793 (.3793) | |
| β-phenethyl | p-Cl | 160 ± 20 (24 ± 9) | 6.667 | 680 ± 240 (1.8K ± 6h) | .3778 | 650 ± 210 (640 ± 60) | 1.016 | 4.25 (75) | .9559 (.3556) | |
| γ-phenpropyl | p-Cl | 290 ± 90 (440 ± 150) | .6591 | 600 ± 140 (490 ± 100) | 1.224 | 1.6K ± 3h (700 ± 200) | .3063 | 2.069 (1.114) | 2.667 (1.429) | |
The most potent compounds in blocking the reuptake of DA were those where R was three or four carbon atoms long.
The 1-propyl side chain has the strongest DAT IC50 value whereas the 1-butyl side chain has the strongest DAT Ki value.
- The 1-butyl side chain has the strongest noradrenaline IC50 whereas neopentyl possesses the strongest Ki at this transporter.
- 4-isopentyl has the greatest NE/DA selectivity.
| Ar | [3H]WIN 35,428 DAT | [3H]DA Uptake | [3H]RTI-55 SERT | Inhibition by 10μM | D.R. | Potency |
|---|---|---|---|---|---|---|
| Ph | 83.9 ± 7.9 | 224 ± 19 | >>10,000 | 19.6 ± 2.5 | 2.7 | 1.00 |
| p-F | 35.0 ± 3.0 | 142 ± 2 | >10,000 | 36.9 ± .8 | 4.1 | 3.33 |
| m-Cl | 5.1 ± 1.6 | 23.0 ± 3.0 | >10,000 | 45.5 ± 3.7 | 4.5 | 2.42 |
| p-Me | 33.0 ± 1.2 | 126 ± 1 | >10,000 | 45.0 ± .5 | 3.8 | .74 |
| p-NH2 | 34.5 ± 4.0 | 114 ± 10 | >>10,000 | 7.9 ± 2.6 | 3.3 | 2.18 |
| p,m-Cl2 | 5.3 ± .7 (2.67 ± .58)b | 7.0 ± .6 | 1,064 ± 62 (>10,000)b | 93.3 ± 2.2 | 1.3 | 7.98 |
| β-Naphthyl | 33.9 ± 6.4b 11.0 ± 2.5c | 53.0 ± 8.0c | 71.6 ± 7.4b | nd | 4.8c | nd |
| Cocaine | 160 ± 15 | 404 ± 26 | 401 ± 27 | nd | 2.5 | .41 |
| aSchweri, et al. (2002); bDavies, et al. (2004); cH.M. Deutsch, et al. (2001). | ||||||
Synthesis and Pharmacology of Ethylphenidate Enantiomers: The Human Transesterification Metabolite of Methylphenidate and Ethanol [5]
Effects of Methylphenidate Analogues on Phenethylamine Substrates for the Striatal Dopamine Transporter. Potential as Amphetamine Antagonists? [6]
Enantioselective Synthesis of D-threo-Methylphenidate[7]
Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites[8]
References
- ↑ [1]Froimowitz, M.; Gu, Y.; Dakin, L. A.; Nagafuji, P. M.; Kelley, C. J.; Parrish, D.; Deschamps, J. R.; Janowsky, A. J. Med. Chem.; (Article); 2007; 50(2); 219-232.
- ↑ [2]Pharmacokinetic Considerations in the Treatment of Attention-Deficit Hyperactivity Disorder with Methylphenidate
- ↑ [3]Synthesis and pharmacology of hydroxylated metabolites of methyl phenidate Kennerly S. Patrick, Clinton D. Kilts, George R. Breese J. Med. Chem.; 1981; 24(10); 1237-1240.
- ↑ [4]European Journal of Pharmacology, Volume 486, Issue 3, 23 February 2004, Pages 251-257
- ↑ [5]Patrick, K. S.; Williard, R. L.; VanWert, A. L.; Dowd, J. J.; Oatis, J. E., Jr.; Middaugh, L. D. J. Med. Chem.; (Article); 2005; 48(8); 2876-2881.
- ↑ [6]Journal of Neurochemistry Volume 72 Issue 3 Page 1266 - March 1999
- ↑ [7]Axten, J. M.; Ivy, R.; Krim, L.; Winkler, J. D. J. Am. Chem. Soc.; (Communication); 1999; 121(27); 6511-6512.
- ↑ [8]Bioorganic & Medicinal Chemistry Letters Volume 14, Issue 7, April 2004, Pages 1799-1802