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Focalin

Introduction

A number of methylphenidate (aka ritalin) analogs were made by H.M. Deutsch, et al. in the mid 1990's with the primary aim of searching for drugs that might have utility in the treatment of cocaine addiction, and the research was therefore funded by NIDA. Likewise, other authors have also followed suit, and a number of synthetic schemes are now available for preparation of these compounds including enantioselective methodology. Due to the fact that methylphenidate has two chiral carbons, the compound exists as a racemic pair of diastereomers. The compounds with threo stereochemistry (TMP) are more active than the corresponding erythro diastereoisomers.

Ritalin is most commonly prescribed for attention deficit disorder (ADHD), although since this compound behaves as a dopamine reuptake inhibitor (DARI), potential drug abuse issues are notwithstanding. It is sometimes referred to by some as an amphetamine derivative.

The purpose of this document is to more generally consider aromatic QSAR information for these monoamine reuptake inhibitors.

Although the in vitro activites of most of the analogs is well characterized, with the exception of the document in 2002 by Schweri et al. much less is known about the in vivo behavioral activity of most of these analogs. It should of course be appreciated that TMP and its analogs are potent psychostimulants with effects that can be paralleled to cocaine. Although certain literature suggests that it is less addictive than cocaine, some of its users have reported that an insufflated dose of TMP is indistinguishable from cocaine in terms of its effects.

Effect of N-demethylation

In contrast to the opioid meperidine which is only modestly active, TMP is a potent stimulant compound. Notice that it is a secondary amine (N-H), and that the corresponding N-Me analog is several-fold weaker and may even possibly be inactive. In the phenyltropane (PT) document, it can be seen that a number of N-demethylated have been prepared and found to be more active than their parent compounds. More explicitly, the N-demethylated series of PT analogs whilst not boosting DAT acitivity, was found to increase the binding affinity at the NET and SERT. This is in contrast to TMP, which is completely devoid of affinity for the SERT. Moreover, the N-demethyl analogs of PT showed an increased seizure risk relative to their N-Me parent compounds. Due to the fact that TMP is already quite a powerful psychostimulant in its own right, it is felt that the p,m-Cl₂ compound amongst other analogs are not required in order to ensure corresponding high activity. Nonetheless the QSAR information is still of a high level of importance from an academic viewpoint and has applications in the design of novel monoamine reuptake inhibitor compounds. There has been interest among some researchers in the β-naphthyl analog in that this compound in addition to being a catecholamine reuptake inhibitor, also possesses affinity for the SERT, and therefore more closely parallels the pharmacology of cocaine. Moreover, the RR enantiomer of the β-naphthyl analog is perhaps even more attractive given that Davies, et al. (2004) recently reported an enantioselective synthesis for this. The fact that it required expensive rhodium catalysts should be viewed as somewhat limiting its widespread application although it is still an interesting compound.

TMP Analogs

The hydrocarbon QSAR study was more of a recent epiphenonema and obscures the real purpose of this document. The synthetic scheme for the hydrocarbon chains are not particularly attractive and if one is interested in this, pyrovalerone based compounds should be preferred.

The following table in this section lays down the QSAR for some of the more common methylphenidate aromatic ring subsitution patterns. In contrast to the QSAR for meperidine analogs, which showed intrinsic SERT affinity, methylphenidate QSAR shows that this class of compounds is predominantly catecholamine selective with respect to the monoamine transporter pumps. This is with the obvious exception of the β-napthyl substitution pattern which does indeed show reasonable SERT affinity. This is in good consonance with the QSAR for the meperidine ring substitution QSAR, although seemingly is not in agreement with the PT's.

^aEffect of (dl-threo) compounds on [3H]WIN and [3H]CIT binding and [3H]DA uptake

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).

Also in good consonance with the meperidine QSAR, is the finding that the p,m-Cl₂ substitution pattern yields not only the most potent compound in the series with respect to the DAT pump, but also the most selective.

Another important distinction that needs to be drawn is the finding that methylphenidate is structurally quite similar to amphetamine since both are β-phenethylamine derived. However, amphetamine based compounds differ from methylphenidate in that their biological mechanism of action works through increasing the release of monoamines into the synaptic cleft (see Rothman, et al. 2006). Contrariwise, methylphenidate is more similar to cocaine and phenyltropane in terms of its biological activity. This judgement is formed on the observation that it is primarily active through inhibitory actions on the monoamine reuptake transporters and therefore increases the synaptic concentration of available monoamine pools via an indirect mechanism, and does not directly facilitate release.

QSAR Hydrocarbon Chain

(Mark Froimowitz, et al. 2007)
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, since the ester group is rapidly hydrolyzed or metabolized to produce the inactive acid. 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).

Inhibition of [¹²⁵I]RTI-55 Binding (Ki, nM) and [³H]Monoamine Uptake (IC50, nM) by (±)-Threo Methylphenidate Diastereoisomers.

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.

Common Literature

Synthesis and Pharmacology of Ethylphenidate Enantiomers: The Human Transesterification Metabolite of Methylphenidate and Ethanol

Effects of Methylphenidate Analogues on Phenethylamine Substrates for the Striatal Dopamine Transporter. Potential as Amphetamine Antagonists?

Enantioselective Synthesis of D-threo-Methylphenidate

Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites