List of methylphenidate analogues


This is a list of methylphenidate analogues, or Phenidates. The most well known compound from this family, methylphenidate, is widely prescribed around the world for the treatment of attention deficit hyperactivity disorder and certain other indications. Several other derivatives including rimiterol, phacetoperane and pipradrol also have more limited medical application. A rather larger number of these compounds have been sold in recent years as designer drugs, either as quasi-legal substitutes for illicit stimulants such as methamphetamine or cocaine, or as purported "study drugs" or nootropics.
More structurally diverse compounds such as Desoxypipradrol, and even mefloquine, 2-benzylpiperidine, rimiterol, enpiroline and DMBMPP, can also be considered structurally related, with the former ones also functionally so, as loosely analogous compounds. The acyl group has sometimes been replaced with similar length ketones to increase duration. Alternatively, the methoxycarbonyl has in some cases been replaced with an alkyl group.
Dozens more phenidates and related compounds are known from the academic and patent literature, and molecular modelling and receptor binding studies have established that the aryl and acyl substituents in the phenidate series are functionally identical to the aryl and acyl groups in the phenyltropane series of drugs, suggesting that the central core of these molecules is primarily acting merely as a scaffold to correctly orientate the binding groups, and for each of the hundreds of phenyltropanes that are known, there may be a phenidate equivalent with a comparable activity profile.

Notable phenidate derivatives

StructureCommon nameChemical nameCAS numberR1R2
2-BZPD2-Benzylpiperidine32838-55-4phenylH
Ritalinic acidPhenylacetic acid19395-41-6phenylCOOH
Ritalinamide2-Phenyl-2-acetamide19395-39-2phenylCONH2
Methylphenidate Methyl phenylacetate113-45-1phenylCOOMe
Phacetoperane methyl] acetate24558-01-8phenylOCOMe
Rimiterol4-benzene-1,2-diol32953-89-23,4-dihydroxyphenylhydroxy
Ethylphenidate Ethyl phenylacetate57413-43-1phenylCOOEt
Propylphenidate Propyl phenylacetate1071564-47-0phenylCOOnPr
Isopropylphenidate Propan-2-yl 2-phenyl-2-acetate93148-46-0phenylCOOiPr
Butylphenidate Butyl phenylacetatephenylCOOnBu
3-Chloromethylphenidate Methyl 2--2-acetate191790-73-53-chlorophenylCOOMe
3-Bromomethylphenidate Methyl 2--2-acetate3-bromophenylCOOMe
4-Fluoromethylphenidate Methyl 2--2-acetate1354631-33-64-fluorophenylCOOMe
4-Fluoroethylphenidate Ethyl 2--2-acetate2160555-59-74-fluorophenylCOOEt
4-Fluoroisopropylphenidate Propan-2-yl 2--2-acetate4-fluorophenylCOOiPr
4-Chloromethylphenidate Methyl 2--2-acetate680996-44-54-chlorophenylCOOMe
3,4-Dichloromethylphenidate Methyl 2--2-acetate1400742-68-83,4-dichlorophenylCOOMe
3,4-Dichloroethylphenidate Ethyl 2--2-acetate3,4-dichlorophenylCOOEt
4-Bromomethylphenidate Methyl 2--2-acetate203056-13-74-bromophenylCOOMe
4-Bromoethylphenidate Ethyl 2--2-acetate1391486-43-34-bromophenylCOOEt
4-Methylmethylphenidate Methyl 2--2-acetate191790-79-14-methylphenylCOOMe
4-Nitromethylphenidate Methyl 2--2-acetate4-nitrophenylCOOMe
Methylenedioxymethylphenidate Methyl acetate3,4-methylenedioxyphenylCOOMe
Methylnaphthidate Methyl acetate231299-82-4naphthalen-2-ylCOOMe
Ethylnaphthidate Ethyl acetatenaphthalen-2-ylCOOEt
MTMPMethyl acetatethiophen-2-ylCOOMe
α-acetyl-2-benzylpiperidine1-Phenyl-1-propan-2-onephenylacetyl
CPMBP2-piperidine3-chlorophenylisobutyl
Desoxypipradrol 2-benzhydrylpiperidine519-74-4phenylphenyl
Pipradrol Diphenylmethanol467-60-7phenylhydroxy,phenyl

;Related compounds
A number of related compounds are known which fit the same general structural pattern, but with substitution on the piperidine ring, or the piperidine ring replaced by other heterocycles such as pyrrolidine, morpholine or quinoline.
StructureCommon nameChemical nameCAS number
SCH-54722-benzhydryl-1-methyl-piperidin-3-ol20068-90-0
Difemetorex2-ethanol13862-07-2
N-benzylethylphenidateEthyl acetate
DMBMPP2--6-piperidine1391499-52-7
Diphenylprolinol diphenylmethanol22348-32-9
2-Benzhydrylpyrrolidine2-pyrrolidine119237-64-8
HDMP-29Methyl acetate
MethylmorphenateMethyl morpholin-3-ylacetate
3-Benzhydrylmorpholine3-morpholine93406-27-0
AL-10952--3-hydroxyquinuclidine54549-19-8
Butyltolylquinuclidine-2-butyl-3-p-tolylquinuclidine

Isomerism

Methylphenidate have two chiral centers, meaning that it, and each of its analogues, have four possible enantiomers, each with differing pharmacokinetics and receptor binding profiles. In practice methylphenidate is most commonly used as pairs of diastereomers rather than isolated single enantiomers or a mixture of all four isomers. Forms include the racemate, the enantiopure of its stereoisomers; erythro or threo among its diastereoisomers, the S,S; S,R/R,S or R,R and, lastly, the isomeric conformers of either its anti- or gauche- rotamer. The variant with optimized efficacy is not the usually attested generic or common pharmaceutical brands but the -dextro--threo-anti, which has a binding profile on par with or better than that of cocaine. Furthermore, the energy to change between its two rotamers involves the stabilizing of the hydrogen bond between the protonated amine with the ester carbonyl resulting in reduced instances of "gauche—gauche" interactions via its favoring for activity the "anti"-conformer for putative homergic-psychostimulating pharmacokinetic properties, postulating that one inherent conformational isomer is necessitated for the activity of the threo diastereoisomer.
Also of note is that methylphenidate in demethylated form is acidic; a metabolite known as ritalinic acid. This gives the potential to yield a conjugate salt form effectively protonated by a salt nearly chemically duplicate/identical to its own structure; creating a "methylphenidate ritalinate".

Receptor binding profiles of selected methylphenidate analogues

[Aryl] substitutions

Both analogues 374 & 375 displayed higher potency than methylphenidate at DAT. In further comparison, 375 was additionally two & a half times more potent than 374.

Aryl exchanged analogues

Piperidine nitrogen methylated phenyl-substituted variants

[Cycloalkane] extensions, contractions & modified derivatives


Methyl 2--2-phenylacetate

Methyl 2--2-phenylacetate
☝The two other potential oxazinane methylphenidate analogues.

Azido-iodo-''N''-benzyl analogues

Structures of Azido-iodo-N-benzyl analogues of methylphenidate with affinities.
StructureCompoundR1R2Ki
IC50
—threo-methylphenidateHH25 ± 1156 ± 58
—4-I-methylphenidatepara-iodoH14 ± 3ɑ11 ± 2b
—3-I-methylphenidatemeta-iodoH4.5 ± 1ɑ14 ± 5b
-----
—p-N3-N-Bn-4-I-methylphenidatepara-iodopara-N3-N-Benzyl363 ± 28ɑ2764 ± 196bc
—m-N3-N-Bn-4-I-methylphenidatepara-iodometa-N3-N-Benzyl2754 ± 169ɑ7966 ± 348bc
—o-N3-N-Bn-4-I-methylphenidatepara-iodoortho-N3-N-Benzyl517 ± 65ɑ1232 ± 70bc
—p-N3-N-Bn-3-I-methylphenidatemeta-iodopara-N3-N-Benzyl658 ± 70ɑ1828 ± 261bc
—m-N3-N-Bn-3-I-methylphenidatemeta-iodometa-N3-N-Benzyl2056 ± 73ɑ4627 ± 238bc
—o-N3-N-Bn-3-I-methylphenidatemeta-iodoortho-N3-N-Benzyl1112 ± 163ɑ2696 ± 178bc
—N-Bn-methylphenidateHN-Benzyl——
—N-Bn-3-chloro-methylphenidate3-ClN-Benzyl——
—N-Bn-3,4-dichloro-methylphenidate3,4-diClN-Benzyl——
—p-chloro-N-Bn-methylphenidateHpara-Cl-N-Benzyl——
—p-methoxy-N-Bn-methylphenidateHpara-OMe-N-Benzyl——
—m-chloro-N-Bn-methylphenidateHmeta-Cl-N-Benzyl——
—p-nitro-N-Bn-methylphenidateHpara-NO2-N-Benzyl——

Two of the compounds tested, the weakest two @ DAT & second to the final two on the table below, were designed to elucidate the necessity of both constrained rings in the efficacy of the below series of compounds at binding by removing one or the other of the two rings in their entirety. The first of the two retain the original piperidine ring had with methylphenidate but has the constrained B ring that is common to the restricted rotational analogues thereof removed. The one below lacks the piperdine ring native to methylphenidate but keeps the ring that hindered the flexibility of the original MPH conformation. Though their potency at binding is weak in comparison to the series, with the potency shared being approximately equal between the two; the latter compound is 8.3-fold more potent @ DA uptake.
CompoundɑR & X substitutionKi
@ DAT with WIN 35,065-2		nH
@ DAT with WIN 35,065-2		Ki or
% inhibition
@ NET with Nisoxetine		nH
@ NET with Nisoxetine		Ki or
% inhibition
@ 5-HTT with Citalopram		nH
@ 5-HTT with Citalopram		DA uptake
IC50 		Selectivity
Citalopram / WIN 35,065-2		Selectivity
Nisoxetine / WIN 35,065-2		Selectivity
Citalopram / Nisoxetine
Cocaine—156 ± 111.03 ± 0.011,930 ± 3600.82 ± 0.05306 ± 131.12 ± 0.15404 ± 262.0120.16
Methylphenidate—74.6 ± 7.40.96 ± 0.08270 ± 230.76 ± 0.0614 ± 8%f—230 ± 16>1303.6>47
3′,4′-dichloro-MPH—4.76 ± 0.622.07 ± 0.05NDh—667 ± 831.07 ± 0.047.00 ± 140140——
-----------
—6,610 ± 4400.91 ± 0.0111%b—3,550 ± 701.79 ± 0.558,490 ± 1,8000.54>0.76<0.7
-----------
H76.2 ± 3.41.05 ± 0.05138 ± 9.01.12 ± 0.205,140 ± 6701.29 ± 0.40244 ± 2.5671.837
3′,4′-diCl3.39 ± 0.771.25 ± 0.2928.4 ± 2.51.56 ± 0.80121 ± 171.16 ± 0.3111.0 ± 0.00368.44.3
2′-Cl480 ± 461.00 ± 0.092,750; 58%b0.961,840 ± 701.18 ± 0.061,260 ± 2903.85.70.67
-----------
—34.6 ± 7.60.95 ± 0.18160 ± 181.28 ± 0.12102 ± 8.21.01 ± 0.0287.6 ± 0.353.04.60.64
-----------
CH2OH2,100 ± 6970.87 ± 0.09NDh—16.2 ± 0.05%f—10,400 ± 530>4.8——
CH37,610 ± 8001.02 ± 0.038.3%b—11 ± 5%f—7,960 ± 290>1.3≫0.66—
-----------
d R=OCH3, X=H570 ± 490.94 ± 0.102,040; 64 ± 1.7%f0.7314 ± 3%f—1,850 ± 160>183.6>4.9
R=OH, X=H6,250 ± 2800.86 ± 0.0323.7 ± 4.1%b—1 ± 1%f—10,700 ± 750≫1.6>0.80—
R=OH, X=3′,4′-diCl35.7 ± 3.21.00 ± 0.09367 ± 421.74 ± 0.872,050 ± 1101.15 ± 0.12NDh57105.6
-----------
H908 ± 1600.88 ± 0.054030; 52%b1.045 ± 1%f—12,400 ± 1,500≫114.4≫2.5
3′,4′-diCl14.0 ± 1.21.27 ± 0.20280 ± 760.68 ± 0.0954 ± 2%f—NDh~71020~36
-----------
R=OH, X=H108 ± 7.00.89 ± 0.10351 ± 850.94 ± 0.2712 ± 2%f—680 ± 52>933.3>28
R=OH, X=3′,4′-diCl2.46 ± 0.521.39 ± 0.2027.9 ± 3.50.70 ± 0.011681.02NDh68116.0
R=OCH3, X=H10.8 ± 0.80.97 ± 0.0763.7 ± 2.80.84 ± 0.042,070; 73 ± 5%f0.9061.0 ± 9.31905.932
-----------
R1=CH3, R2=H178 ± 281.23 ± 0.09694 ± 650.88 ± 0.134271.393682.43.90.62
R1=H, R2=CH3119 ± 201.17 ± 0.1276.0 ± 120.88 ± 0.062431.172482.00.643.2
-----------
—175 ± 8.01.00 ± 0.041,520 ± 1200.97 ± 0.0619 ± 4%f—NDh>578.69>6.6
-----------
R=CH2CH3, X=H27.6 ± 1.71.29 ± 0.05441 ± 491.16 ± 0.192,390; 80%f1.12NDh87155.8
R=CH2CH3, X=3′,4′-diCl3.44 ± 0.021.90 ± 0.05102 ± 191.27 ± 0.10286 ± 471.30 ± 0.10NDh83302.8
-----------
R=CH2CH3, X=H5.51 ± 0.931.15 ± 0.0360.8 ± 9.60.75 ± 0.073,550; 86%f0.95NDh6401158
R=CH2CH3, X=3′,4′-diCl4.12 ± 0.951.57 ± 0.0098.8 ± 8.71.07 ± 0.07199 ± 171.24 ± 0.00NDh48242.0
-----------
—6,360 ± 1,3001.00 ± 0.0436 ± 10%c—22 ± 7%f—8,800 ± 870>1.6——
-----------
i —4,560 ± 1,1001.10 ± 0.09534 ± 210c0.96 ± 0.0853 ± 6%f—1,060 ± 115~2.20.12~19
-----------
R1=CH2OH, R2=H, X=H406 ± 41.07 ± 0.08NDh—31.0 ± 1.5%f—1,520 ± 15>25——
R1=CH2OCH3, R2=H, X=H89.9 ± 9.40.97 ± 0.04NDh—47.8 ± 0.7%f—281 ± 19~110——
R1=CH2OH, R2=H, X=3′,4′-diCl3.91 ± 0.491.21 ± 0.06NDh—276; 94.6%f0.8922.5 ± 1.471——
R1=H, R2=CO2CH3, X=3′,4′-diCl363 ± 201.17 ± 0.41NDh—2,570 ± 5801.00 ± 00.1317 ± 467.1——
R1=CO2CH3, R2=H, X=2′-Cl1,740 ± 2000.98 ± 0.02NDh—22.2 ± 2.5%f—2,660 ± 140>5.7——

Values for dl-threo-methylphenidate derivatives are the mean of 3—6 determinations, or are the mean of duplicate determinations. Values of other compounds are the mean—s.d. for 3—4 determinations where indicated, or are results of single experiments which agree with the literature. All binding experiments were done in triplicate.
CompoundDADA UptakeNE5HT
Methylphenidate84 ± 33153 ± 92514 ± 74>50,000
o-Bromomethylphenidate880 ± 316—20,000—
m-Bromomethylphenidate4 ± 118 ± 1120 ± 63,800
p-Bromomethylphenidate21 ± 345 ± 1931 ± 72,600
p-Hydroxymethylphenidate125263 ± 74270 ± 6917,000
p-Methyloxymethylphenidate42 ± 24490 ± 27041011,000
p-Nitromethylphenidate180—3605,900
p-Iodomethylphenidate26 ± 14—321,800ɑ
m-Iodo-p-hydroxymethylphenidate42 ± 21195 ± 197370 ± 645,900
N-Methylmethylphenidate1,400—2,80040,000
d-threo-Methylphenidate33—244 ± 142>50,000
l-threo-Methylphenidate540—5,100>50,000
dl-erythro-o-Bromomethylphenidate10,000—50,000—
Cocaine120313 ± 1602,100190
WIN 35,42813—53072
Nomifensine29 ± 16—15 ± 21,300ɑ
Mazindol9 ± 5—3 ± 292
Desipramine1,400—3.5200
Fluoxetine3,300—3,4002.4

p-hydroxymethylphenidate displays low brain penetrability, ascribed to its phenolic hydroxyl group undergoing ionization at physiological pH.

Test environment conditioning & control studies