3D molecular rendering of methylphenidate (MPH)

This is a list of methylphenidate (MPH or MPD) 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 (ADHD) 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.[1][2][3]

More structurally diverse compounds such as desoxypipradrol (and thus pipradrol, including such derivatives as AL-1095, diphemethoxidine, SCH-5472 and D2PM), 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.[4][5]

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. Albeit with the respective difference in their entropy of binding: cocaine being −5.6 kcal/mol and methylphenidate being −25.5 kcal/mol (Δs°, measured using [³H]GBR 1278 @ 25 °C).[lower-alpha 1]

Notable phenidate derivatives

General structure of phenidate derivatives, where R is nearly always hydrogen but can be alkyl, R1 is usually phenyl or substituted phenyl but rarely other aryl groups, R2 is usually acyl but can be alkyl or other substitutions, and Cyc is nearly always piperidine but rarely other heterocycles
Structure Common name Chemical name CAS number R1 R2
2-BZPD 2-Benzylpiperidine 32838-55-4 phenyl H
Ritalinic acid Phenyl(piperidin-2-yl)acetic acid 19395-41-6 phenyl COOH
Ritalinamide 2-Phenyl-2-(piperidin-2-yl)acetamide 19395-39-2 phenyl CONH2
Methylphenidate (MPH) Methyl phenyl(piperidin-2-yl)acetate 113-45-1 phenyl COOMe
Phacetoperane (Lidépran) [(R)-phenyl-[(2R)-piperidin-2-yl]methyl] acetate 24558-01-8 phenyl OCOMe
Rimiterol 4-{(S)-hydroxy[(2R)-piperidin-2-yl]methyl}benzene-1,2-diol 32953-89-2 3,4-dihydroxyphenyl hydroxy
Ethylphenidate (EPH) Ethyl phenyl(piperidin-2-yl)acetate 57413-43-1 phenyl COOEt
Propylphenidate (PPH) Propyl phenyl(piperidin-2-yl)acetate 1071564-47-0 phenyl COOnPr
Isopropylphenidate (IPH) Propan-2-yl 2-phenyl-2-(piperidin-2-yl)acetate 93148-46-0 phenyl COOiPr
Butylphenidate (BPH) Butyl phenyl(piperidin-2-yl)acetate phenyl COOnBu
3-Chloromethylphenidate (3-Cl-MPH) Methyl 2-(3-chlorophenyl)-2-(piperidin-2-yl)acetate 191790-73-5 3-chlorophenyl COOMe
3-Bromomethylphenidate (3-Br-MPH) Methyl 2-(3-bromophenyl)-2-(piperidin-2-yl)acetate 3-bromophenyl COOMe
3-Methylmethylphenidate (3-Me-MPH) Methyl 2-(3-methylphenyl)-2-(piperidin-2-yl)acetate 3-methylphenyl COOMe
4-Fluoromethylphenidate (4F-MPH) Methyl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate 1354631-33-6 4-fluorophenyl COOMe
4-Fluoroethylphenidate (4F-EPH) Ethyl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate 2160555-59-7 4-fluorophenyl COOEt
4-Fluoroisopropylphenidate (4F-IPH) Propan-2-yl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate 4-fluorophenyl COOiPr
4-Chloromethylphenidate (4-Cl-MPH) Methyl 2-(4-chlorophenyl)-2-(piperidin-2-yl)acetate 680996-44-5 4-chlorophenyl COOMe
3,4-Dichloromethylphenidate (3,4-DCMP) Methyl 2-(3,4-dichlorophenyl)-2-(piperidin-2-yl)acetate 1400742-68-8 3,4-dichlorophenyl COOMe
3,4-Dichloroethylphenidate (3,4-DCEP) Ethyl 2-(3,4-dichlorophenyl)-2-(piperidin-2-yl)acetate 3,4-dichlorophenyl COOEt
4-Bromomethylphenidate (4-Br-MPH) Methyl 2-(4-bromophenyl)-2-(piperidin-2-yl)acetate 203056-13-7 4-bromophenyl COOMe
4-Bromoethylphenidate (4-Br-EPH) Ethyl 2-(4-bromophenyl)-2-(piperidin-2-yl)acetate 1391486-43-3 4-bromophenyl COOEt
4-Methylmethylphenidate (4-Me-MPH) Methyl 2-(4-methylphenyl)-2-(piperidin-2-yl)acetate 191790-79-1 4-methylphenyl COOMe
4-Methylisopropylphenidate (4-Me-IPH) Propan-2-yl 2-(4-methylphenyl)-2-(piperidin-2-yl)acetate 4-methylphenyl COOiPr
4-Nitromethylphenidate (4-NO2-MPH) Methyl 2-(4-nitrophenyl)-2-(piperidin-2-yl)acetate 4-nitrophenyl COOMe
Methylenedioxymethylphenidate (MDMPH) Methyl (1,3-benzodioxol-5-yl)(piperidin-2-yl)acetate 3,4-methylenedioxyphenyl COOMe
Methylnaphthidate (HDMP-28) Methyl (naphthalen-2-yl)(piperidin-2-yl)acetate 231299-82-4 naphthalen-2-yl COOMe
Ethylnaphthidate (HDEP-28) Ethyl (naphthalen-2-yl)(piperidin-2-yl)acetate 2170529-69-6 naphthalen-2-yl COOEt
Isopropylnaphthidate Propan-2-yl (naphthalen-2-yl)(piperidin-2-yl)acetate naphthalen-2-yl COOiPr
MTMP Methyl (thiophen-2-yl)(piperidin-2-yl)acetate thiophen-2-yl COOMe
α-acetyl-2-benzylpiperidine 1-Phenyl-1-(piperidin-2-yl)propan-2-one phenyl acetyl
CPMBP 2-[1-(3-chlorophenyl)-3-methylbutyl]piperidine 3-chlorophenyl isobutyl
Desoxypipradrol (2-DPMP) 2-benzhydrylpiperidine 519-74-4 phenyl phenyl
Pipradrol (Meratran) Diphenyl(piperidin-2-yl)methanol 467-60-7 phenyl hydroxy,phenyl
Related compounds

A number of related compounds are known which fit the same general structural pattern, but with substitution on the piperidine ring (e.g. SCH-5472, Difemetorex, N-benzylethylphenidate), or the piperidine ring replaced by other heterocycles such as pyrrolidine (e.g. diphenylprolinol, 2-Diphenylmethylpyrrolidine), morpholine (e.g. Methylmorphenate, 3-Benzhydrylmorpholine) or quinoline (e.g. AL-1095, Butyltolylquinuclidine).

Structure Common name Chemical name CAS number
SCH-5472 2-benzhydryl-1-methyl-piperidin-3-ol 20068-90-0
Difemetorex 2-[2-(diphenylmethyl)piperidin-1-yl]ethanol 13862-07-2
N-benzylethylphenidate Ethyl (1-benzylpiperidin-2-yl)(phenyl)acetate
Serdexmethylphenidate (1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium-3-carbonyl)-L-serinate chloride 1996626-30-2
DMBMPP 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine 1391499-52-7
Diphenylprolinol (D2PM) diphenyl(pyrrolidin-2-yl)methanol 22348-32-9
2-Benzhydrylpyrrolidine 2-(Diphenylmethyl)pyrrolidine 119237-64-8
HDMP-29 Methyl (naphthalen-2-yl)(pyrrolidin-2-yl)acetate
Methylmorphenate Methyl morpholin-3-yl(phenyl)acetate
3-Benzhydrylmorpholine 3-(diphenylmethyl)morpholine 93406-27-0
AL-1095 2-(1-phenyl-1-(p-chlorophenyl)methyl)-3-hydroxyquinuclidine 54549-19-8
Butyltolylquinuclidine (2R,3S,4S)-2-butyl-3-p-tolylquinuclidine

Isomerism

Alternate two dimensional rendering of "D-threo-methylphenidate"; demonstrating the plasticity of the piperidine ring in a 'flexed' or "chair" conformation. (the latter term can denote a structure containing a bridge in the ring when so-named, unlike the above).

N.B. although the cyclohexane conformation, if considering both the hydrogen on the plain bond and the implicit carbon on the dotted bond are not shown as positioned as would be for the least energy state inherent to what rules apply, internally, to the molecule in and of itself: possibility of movement between putative other ligand sites in suchwise, here regarding what circumstance allows for describing it as "flexed" thus mean it has shown tendency for change in situ depending on its environment and adjacent sites of potential interaction as against its least energy state.

Methylphenidate (and its derivatives) 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 (dextro or levo) of its stereoisomers; erythro or threo (either + or -) among its diastereoisomers, the chiral isomers S,S; S,R/R,S or R,R and, lastly, the isomeric conformers (which are not absolute) of either its anti- or gauche- rotamer. The variant with optimized efficacy is not the usually attested generic or common pharmaceutical brands (e.g. Ritalin, Daytrana etc.) but the (R,R)-dextro-(+)-threo-anti (sold as Focalin), which has a binding profile on par with or better than that of cocaine.[lower-alpha 2] (Note however the measure of fivefold (5×) discrepancy in the entropy of binding at their presumed shared target binding site, which may account for the higher abuse potential of cocaine over methylphenidate despite affinity for associating; i.e the latter dissociates more readily once bound despite efficacy for binding.[lower-alpha 3]) Furthermore, the energy to change between its two rotamers involves the stabilizing of the hydrogen bond between the protonated amine (of an 8.5 pKa) 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 ("anti") is necessitated for the activity of the threo diastereoisomer.[lower-alpha 4]

Also of note is that methylphenidate in demethylated form is acidic; a metabolite (and precursor) known as ritalinic acid.[8] This gives the potential to yield a conjugate salt[9] form effectively protonated by a salt nearly chemically duplicate/identical to its own structure; creating a "methylphenidate ritalinate".[10]

Receptor binding profiles of selected methylphenidate analogues

Aryl substitutions

Phenyl ring substituted methylphenidate analogues[lower-alpha 5]
Compound S. Singh's
alphanumeric
assignation
(name)		 R1 R2 IC50 (nM)
(Inhibition of [3H]WIN 35428 binding)		 IC50 (nM)
(Inhibition of [3H]DA uptake)		 Selectivity
uptake/binding
(D-threo-methylphenidate)H, H33244 ± 142
(171 ± 10)		7.4
(L-threo-methylphenidate)5405100
(1468 ± 112)		9.4
(D/L-threo-methylphenidate)
"eudismic ratio"		6.420.9
(8.6)		-
(DL-threo-methylphenidate)83.0 ± 7.9224 ± 192.7
(R-benzoyl-methylecgonine)
(cocaine)		(H, H)173 ± 13404 ± 262.3
351a (4F-MPH)FH
y
d
r
o
g
e
n
i.e.
H		35.0 ± 3.0142 ± 2.04.1
351bCl20.6 ± 3.473.8 ± 8.13.6
351cBr6.9 ± 0.126.3 ± 5.83.8
351d(d) Br-22.5 ± 2.1-
351e(l) Br-408 ± 17-
351d/e
"eudismic ratio"		(d/l) Br-18.1-
351fI14.0 ± 0.164.5 ± 3.54.6
351gOH98.0 ± 10340 ± 703.5
351hOCH383 ± 11293 ± 483.5
351i(d) OCH3-205 ± 10-
351j(l) OCH3-3588 ± 310-
351i/j
"eudismic ratio"		(d/l) OCH3-17.5-
351k (4-Me-MPH)CH333.0 ± 1.2126 ± 13.8
351lt-Bu13500 ± 4509350 ± 9500.7
351mNH2.HCl34.6 ± 4.0115 ± 103.3
351nNO2494 ± 331610 ± 2103.3
352aF40.5 ± 4.5160 ± 0.004.0
352bCl5.1 ± 1.623.0 ± 3.04.5
352cBr4.2 ± 0.212.8 ± 0.203.1
352dOH321 ± 1.0790 ± 302.5
352eOMe288 ± 53635 ± 350.2
352fMe21.4 ± 1.1100 ± 184.7
352gNH2.HCl265 ± 5578 ± 1602.2
353a2′-F1420 ± 1202900 ± 3002.1
353b2′-Cl1950 ± 2302660 ± 1401.4
353c2′-Br1870 ± 1353410 ± 2901.8
353d2′-OH23100 ± 5035,800 ± 8001.6
353e2′-OCH3101,000 ± 10,00081,000 ± 20000.8
354a (3,4-DCMP)Cl, Cl
(3′,4′-Cl2)		5.3 ± 0.77.0 ± 0.61.3
354bIOH42 ± 21195 ± 1974.6
354cOMe, OMe
(3′,4′-OMe2)		810 ± 101760 ± 1602.2

Both analogues 374 & 375 displayed higher potency than methylphenidate at DAT. In further comparison, 375 (the 2-naphthyl) was additionally two & a half times more potent than 374 (the 1-naphthyl isomer).[lower-alpha 6]

Aryl exchanged analogues

Phenyl ring modified methylphenidate analogues[lower-alpha 7]
Compound S. Singh's
alphanumeric
assignation
(name)		 Ring Ki (nM)
(Inhibition of [125I]IPT binding)		 Ki (nM)
(Inhibition of [3H]DA uptake)		 Selectivity
uptake/binding
(D-threo-methylphenidate)benzene324--
(DL-threo-methylphenidate)82 ± 77429 ± 880.7
3741-naphthalene194 ± 151981 ± 44310.2
375
(HDMP-28)		2-naphthalene79.585.2 ± 251.0
376benzyl>5000--
HDMP-29, a manifold (multiple augmented) analogue of both the phenyl (to a 2-naphthalene) and piperidine (to a 2-pyrrolidine) rings.[11]

Piperidine nitrogen methylated phenyl-substituted variants

N-methyl phenyl ring substituted methylphenidate analogues[lower-alpha 8]
Compound S. Singh's
alphanumeric
assignation
(name)		 R IC50 (nM)
(Inhibition of binding at DAT)
373aH500 ± 25
373b4″-OH1220 ± 140
373c4″-CH3139 ± 13
373d3″-Cl161 ± 18
373e3″-Me108 ± 16
HDEP-28, Ethylnaphthidate.

Cycloalkane extensions, contractions & modified derivatives

Piperidine ring modified methylphenidate analogues[lower-alpha 9]
Compound S. Singh's
alphanumeric
assignation
(name)		 Cycloalkane
ring		 Ki (nM)
(Inhibition of binding)
3802-pyrrolidine
(cyclopentane)		1336 ± 108
3812-azepane
(cycloheptane)		1765 ± 113
3822-azocane
(cyclooctane)		3321 ± 551
3834-1,3-oxazinane
(cyclohexane)		6689 ± 1348

Methyl 2-(1,2-oxazinan-3-yl)-2-phenylacetate

Methyl 2-(1,3-oxazinan-2-yl)-2-phenylacetate
☝The two other (in addition to compound 383) potential oxazinane methylphenidate analogues.

Methyl 2-phenyl-2-(morpholin-3-yl)acetate
A.K.A. Methyl 2-morpholin-3-yl-2-phenylacetate		☜Methylmorphenate methylphenidate analogue.[12]

Azido-iodo-N-benzyl analogues

Structures of Azido-iodo-N-benzyl analogues of methylphenidate with affinities.[13]

Azido-iodo-N-benzyl methylphenidate analogs inhibitition of [3H]WIN 35428 binding and [3H]dopamine uptake at hDAT N2A neuroblastoma cells.[13]
(Each Ki or IC50 value represents data from at least three independent experiments with each data point on the curve performed in duplicate)
Structure Compound R1 R2 Ki (nM)
(Inhibition of [3H]WIN 35428 binding)		 IC50 (nM)
(Inhibition of [3H]DA uptake)
(±)—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——
  • ɑp <0.05 versus Ki of (±)—threo-methylphenidate.
  • bp <0.05 versus IC50 of (±)—threo-methylphenidate.
  • cp <0.05 versus its corresponding Ki.
Additional arene/nitrogen-linked MPH analogs
ChEMBL1254008[14]
ChEMBL1255099[15]

Alkyl substituted-carbomethoxy analogues

Alkyl RR/SS diastereomer analogs of methylphenidate[4]
(RS/SR diastereomer values of otherwise same compounds given in small grey typeface[4])
Structure R1 R2 R3 Dopamine transporter Ki (nM)
(Inhibition of [I125H]RTI-55 binding)		 DA uptake
IC50 (nM)		 Serotonin transporter Ki (nM)
(Inhibition of [I125H]RTI-55 binding)		 5HT uptake
IC50 (nM)		 Norepinephrine transporter Ki (nM)
(Inhibition of [I125H]RTI-55 binding)		 NE uptake
IC50 (nM)		 NE/DA selectivity
(binding displacement)		 NE/DA selectivity
(uptake blocking)
Cocaine—
ɑ		—
b		—
c		500 ± 65240 ± 15340 ± 40250 ± 40500 ± 90210 ± 301.00.88
HCOOCH3H110 ± 979 ± 1665,000 ± 4,0005,100 ± 7,000660 ± 5061 ± 146.00.77
4-chloroCOOCH3H25 ± 8
2,000 ± 600		11 ± 28
2,700 ± 1,000		6,000 ± 100
5,900 ± 200		>9,800
>10 mM		110 ± 40
>6,100		11 ± 3
1,400 ± 400		4.41.0
4-chloromethylH180 ± 70
>3,900		22 ± 7
1,500 ± 700		4,900 ± 500
>9,100		1,900 ± 300
4,700 ± 800		360 ± 140
>6,300		35 ± 13
3,200 ± 800		2.01.6
4-chloroethylH37 ± 10
1,800 ± 300		23 ± 5
2,800 ± 700		7,800 ± 800
4,200 ± 400		2,400 ± 400
4,100 ± 1,000		360 ± 60
>9,200		210 ± 30
1,300 ± 400		9.79.1
4-chloropropylH11 ± 3
380 ± 40		7.4 ± 0.4
450 ± 60		2,700 ± 600
3,200 ± 1,100		2,900 ± 1,100
1,300 ± 7		200 ± 80
1,400 ± 400		50 ± 15
200 ± 50		18.06.8
4-chloroisopropylH46 ± 16
900 ± 320		32 ± 6
990 ± 280		5,300 ± 1,300
>10 mM		3,300 ± 400
—		810 ± 170
>10 mM		51 ± 20
—		18.01.6
4-chlorobutylH7.8 ± 1.1
290 ± 70		8.2 ± 2.1
170 ± 40		4,300 ± 400
4,800 ± 700		4,000 ± 400
3,300 ± 600		230 ± 30
1,600 ± 300		26 ± 7
180 ± 60		29.03.2
4-chloroisobutylH16 ± 4
170 ± 50		8.6 ± 2.9
380 ± 130		5,900 ± 900
4,300 ± 500		490 ± 80
540 ± 150		840 ± 130
4,500 ± 1,500		120 ± 40
750 ± 170		53.014.0
4-chloropentylH23 ± 7
870 ± 140		45 ± 14
650 ± 20		2,200 ± 100
3,600 ± 1,000		1,500 ± 300
1,700 ± 700		160 ± 40
1,500 ± 300		49 ± 16
860 ± 330		7.01.1
4-chloroisopentylH3.6 ± 1.2
510 ± 170		14 ± 2
680 ± 120		5,000 ± 470
6,700 ± 500		7,300 ± 1,400
>8,300		830 ± 110
12,000 ± 1,400		210 ± 40
3,000 ± 540		230.015.0
4-chloroneopentylH120 ± 40
600 ± 40		60 ± 2
670 ± 260		3,900 ± 500
3,500 ± 1,000		>8,300
1,800 ± 600		1,400 ± 400
>5,500		520 ± 110
730 ± 250		12.08.7
4-chlorocyclopentylmethylH9.4 ± 1.5
310 ± 80		21 ± 1
180 ± 20		2,900 ± 80
3,200 ± 700		2,100 ± 900
5,600 ± 1,400		1,700 ± 600
2,600 ± 800		310 ± 40
730 ± 230		180.015.0
4-chlorocyclohexylmethylH130 ± 40
260 ± 30		230 ± 70
410 ± 60		900 ± 400
3,700 ± 500		1,000 ± 200
6,400 ± 1,300		4,200 ± 200
4,300 ± 200		940 ± 140
1,700 ± 600		32.04.1
4-chlorobenzylH440 ± 110
550 ± 60		370 ± 90
390 ± 60		1,100 ± 200
4,300 ± 800		1,100 ± 200
4,700 ± 500		2,900 ± 800
4,000 ± 800		2,900 ± 600
>8,800		6.67.8
4-chlorophenethylH24 ± 9
700 ± 90		160 ± 20
420 ± 140		640 ± 60
1,800 ± 70		650 ± 210
210 ± 900d		1,800 ± 600
2,400 ± 700		680 ± 240
610 ± 150		75.04.3
4-chlorophenpropylH440 ± 150
2,900 ± 900		290 ± 90
1,400 ± 400		700 ± 200
1,500 ± 200		1,600 ± 300
1,200 ± 400		490 ± 100
1,500 ± 200		600 ± 140
1,700 ± 200		1.12.1
4-chloro3-pentylH400 ± 80
>5,700		240 ± 60
1,200 ± 90		3,900 ± 300
4,800 ± 1,100		>9,400
>9,600		970 ± 290
4,300 ± 200		330 ± 80
3,800 ± 30		2.41.4
4-chlorocyclopentylH36 ± 10
690 ± 140		27 ± 8.3
240 ± 30		5,700 ± 1,100
4,600 ± 700		4,600 ± 800
4,200 ± 900		380 ± 120
3,300 ± 800		44 ± 18
1,000 ± 300		11.01.6
3-chloroisobutylH3.7 ± 1.1
140 ± 30		2.8 ± 0.4
88 ± 12		3,200 ± 400
3,200 ± 400		2,100 ± 100
870 ± 230		23 ± 6
340 ± 50		14 ± 1
73 ± 5		6.25.0
3,4-dichloroCOOCH3H1.4 ± 0.1
90 ± 14		23 ± 3
800 ± 110		1,600 ± 150
2,500 ± 420		540 ± 110
1,100 ± 90		14 ± 6
4,200 ± 1,900		10 ± 1
190 ± 50		10.00.43
3,4-dichloropropylH0.97 ± 0.31
43 ± 9		4.5 ± 0.4
88 ± 32		1,800 ± 500
450 ± 80		560 ± 120
180 ± 60		3.9 ± 1.4
30 ± 8		8.1 ± 3.8
47 ± 22		4.01.8
3,4-dichlorobutylH2.3 ± 0.2
29 ± 5		5.7 ± 0.5
67 ± 13		1,300 ± 300
1,100 ± 200		1,400 ± 300
550 ± 80		12 ± 3
31 ± 11		27 ± 10
63 ± 27		5.24.7
3,4-dichloroisobutylH1.0 ± 0.5
31 ± 11		5.5 ± 1.3
13 ± 3		1,600 ± 100
450 ± 40		1,100 ± 300
290 ± 60		25 ± 9
120 ± 30		9.0 ± 1.2
19 ± 3		25.01.6
3,4-dichloroisobutylCH36.6 ± 0.9
44 ± 12		13 ± 4
45 ± 4		1,300 ± 200
1,500 ± 300		1,400 ± 500
2,400 ± 700		190 ± 60
660 ± 130		28 ± 3
100 ± 19		29.02.2
4-methoxyisobutylH52 ± 16
770 ± 220		25 ± 9
400 ± 120		2,800 ± 600
950 ± 190		3,500 ± 500
1,200 ± 300		3,100 ± 200
16,000 ± 2,000		410 ± 90
1,600 ± 400		60.016.0
3-methoxyisobutylH22 ± 5
950 ± 190		35 ± 12
140 ± 20		4,200 ± 400
3,800 ± 600		2,700 ± 800
2,600 ± 300		3,800 ± 500
12,000 ± 2,300		330 ± 40
1,400 ± 90		170.09.4
4-isopropylisobutylH3,300 ± 600
>6,500		4,000 ± 400
>9,100		3,300 ± 600
1,700 ± 500		4,700 ± 700
1,700 ± 100		2,500 ± 600
3,200 ± 600		7,100 ± 1,800
>8,700		0.761.8
HCOCH3H370 ± 70190 ± 507,800 ± 1,200>9,7002,700 ± 400220 ± 307.31.2
  • ɑH = Equivalent overlay of structure sharing functional group
  • bCO2CH3 (i.e. COOCH3) = Equivalent overlay of structure sharing functional group
  • cCH3 = Equivalent overlay of structure sharing functional group
  • dpossible typographical error in original source; e.g. 2,100 ± 900 or 900 ± 210

Restricted rotational analogs of methylphenidate (quinolizidines)

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 (the one more nearly resembling the substrate class of dopaminergic releasing agents similar to phenmetrazine) is 8.3-fold more potent @ DA uptake.

Binding assaysg of rigid methylphenidate analogues[16]
Compoundɑ R & X substitution(s) Ki (nM)
@ DAT with [33]WIN 35,065-2		 nH
@ DAT with [33]WIN 35,065-2		 Ki (nM) or
% inhibition
@ NET with [33]Nisoxetine		 nH
@ NET with [33]Nisoxetine		 Ki (nM) or
% inhibition
@ 5-HTT with [33]Citalopram		 nH
@ 5-HTT with [33]Citalopram		 [33]DA uptake
IC50 (nM)		 Selectivity
[33]Citalopram / [33]WIN 35,065-2		 Selectivity
[33]Nisoxetine / [33]WIN 35,065-2		 Selectivity
[33]Citalopram / [33]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——
  • ɑCompounds tested as hydroclhoride (HCl) salts, unless otherwise noted.
  • b% inhibition caused by 5μM
  • c% inhibition caused by 10μM, as assayed by SRI
  • dTested as free base
  • eAssayed by SRI (appropriate correction factor applied.)
  • f% inhibition of 10μM compound.
  • gValues expressed as x ± SEM of 2—5 replicate tests. (If no SEM shown, value is for an n of 1.)
  • hNot determined
  • icf. phenmetrazine & derivatives

Various MPH congener affinity values inclusive of norepinephrine & serotonin

Values for dl-threo-methylphenidate derivatives are the mean (s.d.)[17] 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.[18]

Binding and uptake IC50 (nM) values for MAT.
Compound DA DA Uptake NE 5HT
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
  • ɑDenotes that preparation of membrane and results extrapolated therefrom originated from frozen tissue, which is known to change results when interpreting against fresh tissue experiments.

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

See also

HDMP-28 molecular model superimposed over β-CFT. cf. cocaine, and the phenyltropane class of drugs, including all subsets of related derivatives for either as pertaining in similarity to methylphenidate analogs.
Methylphenidate rendered in 3D (in blue) overlaid with 1-(2-Phenylethyl) piperazine skeleton (turquoise) showing the basic 3- point pharmacophore shared between them and other dopamine reuptake inhibitors such as 3C-PEP (which in turn is structurally related to the GBR stimulant compounds.)

References

  1. ↑ Klare H, Neudörfl JM, Brandt SD, Mischler E, Meier-Giebing S, Deluweit K, Westphal F, Laussmann T. Analysis of six 'neuro-enhancing' phenidate analogs. Drug Test Anal. 2017 Mar;9(3):423-435. Klare H, Neudörfl JM, Brandt SD, Mischler E, Meier-Giebing S, Deluweit K, et al. (March 2017). "Analysis of six 'neuro-enhancing' phenidate analogs" (PDF). Drug Testing and Analysis. 9 (3): 423–435. doi:10.1002/dta.2161. PMID 28067464.
  2. ↑ Luethi D, Kaeser PJ, Brandt SD, Krähenbühl S, Hoener MC, Liechti ME. Pharmacological profile of methylphenidate-based designer drugs. Neuropharmacology. 2018 May 15;134(Pt A):133-140. Luethi D, Kaeser PJ, Brandt SD, Krähenbühl S, Hoener MC, Liechti ME (May 2018). "Pharmacological profile of methylphenidate-based designer drugs" (PDF). Neuropharmacology. 134 (Pt A): 133–140. doi:10.1016/j.neuropharm.2017.08.020. PMID 28823611. S2CID 207233576.
  3. ↑ Carlier J, Giorgetti R, Varì MR, Pirani F, Ricci G, Busardò FP. Use of cognitive enhancers: methylphenidate and analogs. Eur Rev Med Pharmacol Sci. 2019 Jan;23(1):3-15. Carlier J, Giorgetti R, Varì MR, Pirani F, Ricci G, Busardò FP (January 2019). "Use of cognitive enhancers: methylphenidate and analogs". European Review for Medical and Pharmacological Sciences. 23 (1): 3–15. doi:10.26355/eurrev_201901_16741. PMID 30657540. S2CID 58643522.
  4. 1 2 3 Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, et al. (January 2007). "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". Journal of Medicinal Chemistry. 50 (2): 219–32. doi:10.1021/jm0608614. PMID 17228864.
  5. ↑ Misra M, Shi Q, Ye X, Gruszecka-Kowalik E, Bu W, Liu Z, Schweri MM, Deutsch HM, Venanzi CA (2010). "Quantitative structure-activity relationship studies of threo-methylphenidate analogs". Bioorg Med Chem. 18 (20): 7221–38. doi:10.1016/j.bmc.2010.08.034. PMID 20846865.
  6. ↑ Singh, Satendra; et al. (2000). "Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists" (PDF). Chem. Rev. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256.
  7. 1 2 3 4 5 6 7 8 Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists" (PDF). Chemical Reviews. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256.
  8. ↑ Marchei E, Farré M, Pardo R, Garcia-Algar O, Pellegrini M, Pacifici R, Pichini S (April 2010). "Correlation between methylphenidate and ritalinic acid concentrations in oral fluid and plasma". Clinical Chemistry. 56 (4): 585–92. doi:10.1373/clinchem.2009.138396. PMID 20167695.
  9. ↑ US 20040180928, Gutman A, Zaltsman I, Shalimov A, Sotrihin M, Nisnevich G, Yudovich L, Fedotev I, "Process for the preparation of dexmethylphenidate hydrochloride", published 16 September 2004, assigned to ISP Investments LLC
  10. ↑ US 6441178, Shahriari H, Gerard Z, Potter A, "Resolution of ritalinic acid salt", published 27 August 2002, assigned to Medeva Europe Ltd
  11. ↑ Lile JA, Wang Z, Woolverton WL, France JE, Gregg TC, Davies HM, Nader MA (October 2003). "The reinforcing efficacy of psychostimulants in rhesus monkeys: the role of pharmacokinetics and pharmacodynamics". The Journal of Pharmacology and Experimental Therapeutics. 307 (1): 356–66. doi:10.1124/jpet.103.049825. PMID 12954808. S2CID 5654856.
  12. ↑ "Compound Summary for CID 85054562". PubChem. U.S. National Library of Medicine.
  13. 1 2 Lapinsky DJ, Velagaleti R, Yarravarapu N, Liu Y, Huang Y, Surratt CK, et al. (January 2011). "Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling". Bioorganic & Medicinal Chemistry. 19 (1): 504–12. doi:10.1016/j.bmc.2010.11.002. PMC 3023924. PMID 21129986.
  14. ↑ "ChEMBL1254008". ChEMBL database. European Bioinformatics Institute (EMBL-EBI).
  15. ↑ "ChEMBL1255099". ChEMBL database. European Bioinformatics Institute (EMBL-EBI).
  16. ↑ Kim DI, Deutsch HM, Ye X, Schweri MM (May 2007). "Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate". Journal of Medicinal Chemistry. 50 (11): 2718–31. doi:10.1021/jm061354p. PMID 17489581.
  17. ↑ Jaykaran (October 2010). ""Mean ± SEM" or "Mean (SD)"?". Indian Journal of Pharmacology. 42 (5): 329. doi:10.4103/0253-7613.70402. PMC 2959222. PMID 21206631.
  18. ↑ Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS (1996). "Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters". Life Sciences. 58 (12): 231–9. doi:10.1016/0024-3205(96)00052-5. PMID 8786705.

Notes

  1. ↑ [6] ←Page #1,006 (82nd page of article) 2nd row, 1st ¶ (orig. ref.: Bonnet, J.-J.; Benmansour, S.; Costenin, J.; Parker, E. M. ;Cubeddu, L. X. J. Pharmacol. Exp. Ther. 1990, 253, 1206)
  2. ↑ [7] ←Page #1,005 (81st page of article) §VI. Final ¶.
  3. ↑ [7] ←Page #1,006 (82nd page of article) 2nd column, end of first ¶.
  4. ↑ [7] ←Page #1,005 (81st page of article) Final § (§VI.) & page #1,006 (82nd page of article) left (1st) column, first ¶ and figure 51.
  5. ↑ [7] ←Page #1,010 (86th page of article) Table 47, Page #1,007 (83rd page of article) Figure 52
  6. ↑ [7] ←Page #1,010 (86th page of article) 2nd ¶, lines 2, 3 & 5.
  7. ↑ [7] ←Page #1,010 (86th page of article) Table 49, Page #1,007 (83rd page of article) Figure 54
  8. ↑ [7] ←Page #1,010 (86th page of article) Table 48, Page #1,007 (83rd page of article) Figure 53
  9. ↑ [7] ←Page #1,011 (87th page of article) Table 50, Page #1,007 (83rd page of article) Figure 55

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