List of methylphenidate analogues

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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).[a]

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.[b] (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.[c]) 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.[d]

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[e]
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, H 33 244 ± 142
(171 ± 10)
7.4
(L-threo-methylphenidate) 540 5100
(1468 ± 112)
9.4
(D/L-threo-methylphenidate)
"eudismic ratio"
6.4 20.9
(8.6)
-
(DL-threo-methylphenidate) 83.0 ± 7.9 224 ± 19 2.7
(R-benzoyl-methylecgonine)
(cocaine)
(H, H) 173 ± 13 404 ± 26 2.3
351a (4F-MPH) F H
y
d
r
o
g
e
n
i.e.
H
35.0 ± 3.0 142 ± 2.0 4.1
351b Cl 20.6 ± 3.4 73.8 ± 8.1 3.6
351c Br 6.9 ± 0.1 26.3 ± 5.8 3.8
351d (d) Br - 22.5 ± 2.1 -
351e (l) Br - 408 ± 17 -
351d/e
"eudismic ratio"
(d/l) Br - 18.1 -
351f I 14.0 ± 0.1 64.5 ± 3.5 4.6
351g OH 98.0 ± 10 340 ± 70 3.5
351h OCH3 83 ± 11 293 ± 48 3.5
351i (d) OCH3 - 205 ± 10 -
351j (l) OCH3 - 3588 ± 310 -
351i/j
"eudismic ratio"
(d/l) OCH3 - 17.5 -
351k (4-Me-MPH) CH3 33.0 ± 1.2 126 ± 1 3.8
351l t-Bu 13500 ± 450 9350 ± 950 0.7
351m NH2.HCl 34.6 ± 4.0 115 ± 10 3.3
351n NO2 494 ± 33 1610 ± 210 3.3
352a F 40.5 ± 4.5 160 ± 0.00 4.0
352b Cl 5.1 ± 1.6 23.0 ± 3.0 4.5
352c Br 4.2 ± 0.2 12.8 ± 0.20 3.1
352d OH 321 ± 1.0 790 ± 30 2.5
352e OMe 288 ± 53 635 ± 35 0.2
352f Me 21.4 ± 1.1 100 ± 18 4.7
352g NH2.HCl 265 ± 5 578 ± 160 2.2
353a 2-F 1420 ± 120 2900 ± 300 2.1
353b 2-Cl 1950 ± 230 2660 ± 140 1.4
353c 2-Br 1870 ± 135 3410 ± 290 1.8
353d 2-OH 23100 ± 50 35,800 ± 800 1.6
353e 2-OCH3 101,000 ± 10,000 81,000 ± 2000 0.8
354a (3,4-DCMP) Cl, Cl
(3,4-Cl2)
5.3 ± 0.7 7.0 ± 0.6 1.3
354b I OH 42 ± 21 195 ± 197 4.6
354c OMe, OMe
(3,4-OMe2)
810 ± 10 1760 ± 160 2.2

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).[f]

Aryl exchanged analogues

Phenyl ring modified methylphenidate analogues[g]
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) benzene 324 - -
(DL-threo-methylphenidate) 82 ± 77 429 ± 88 0.7
374 1-naphthalene 194 ± 15 1981 ± 443 10.2
375
(HDMP-28)
2-naphthalene 79.5 85.2 ± 25 1.0
376 benzyl >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[h]
Compound S. Singh's
alphanumeric
assignation
(name)
R IC50 (nM)
(Inhibition of binding at DAT)
373a H 500 ± 25
373b 4″-OH 1220 ± 140
373c 4″-CH3 139 ± 13
373d 3″-Cl 161 ± 18
373e 3″-Me 108 ± 16
HDEP-28, Ethylnaphthidate.

Cycloalkane extensions, contractions & modified derivatives

Piperidine ring modified methylphenidate analogues[i]
Compound S. Singh's
alphanumeric
assignation
(name)
Cycloalkane
ring
Ki (nM)
(Inhibition of binding)
380 2-pyrrolidine
(cyclopentane)
1336 ± 108
381 2-azepane
(cycloheptane)
1765 ± 113
382 2-azocane
(cyclooctane)
3321 ± 551
383 4-1,3-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-methylphenidate H H 25 ± 1 156 ± 58
(±)—4-I-methylphenidate para-iodo H 14 ± 3ɑ 11 ± 2b
(±)—3-I-methylphenidate meta-iodo H 4.5 ± 1ɑ 14 ± 5b
(±)—p-N3-N-Bn-4-I-methylphenidate para-iodo para-N3-N-Benzyl 363 ± 28ɑ 2764 ± 196bc
(±)—m-N3-N-Bn-4-I-methylphenidate para-iodo meta-N3-N-Benzyl 2754 ± 169ɑ 7966 ± 348bc
(±)—o-N3-N-Bn-4-I-methylphenidate para-iodo ortho-N3-N-Benzyl 517 ± 65ɑ 1232 ± 70bc
(±)—p-N3-N-Bn-3-I-methylphenidate meta-iodo para-N3-N-Benzyl 658 ± 70ɑ 1828 ± 261bc
(±)—m-N3-N-Bn-3-I-methylphenidate meta-iodo meta-N3-N-Benzyl 2056 ± 73ɑ 4627 ± 238bc
(±)—o-N3-N-Bn-3-I-methylphenidate meta-iodo ortho-N3-N-Benzyl 1112 ± 163ɑ 2696 ± 178bc
(±)—N-Bn-methylphenidate H N-Benzyl
(±)—N-Bn-3-chloro-methylphenidate 3-Cl N-Benzyl
(±)—N-Bn-3,4-dichloro-methylphenidate 3,4-diCl N-Benzyl
(±)—p-chloro-N-Bn-methylphenidate H para-Cl-N-Benzyl
(±)—p-methoxy-N-Bn-methylphenidate H para-OMe-N-Benzyl
(±)—m-chloro-N-Bn-methylphenidate H meta-Cl-N-Benzyl
(±)—p-nitro-N-Bn-methylphenidate H para-NO2-N-Benzyl
  • ɑ p <0.05 versus Ki of (±)—threo-methylphenidate.
  • b p <0.05 versus IC50 of (±)—threo-methylphenidate.
  • c p <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 ± 65 240 ± 15 340 ± 40 250 ± 40 500 ± 90 210 ± 30 1.0 0.88
H COOCH3 H 110 ± 9 79 ± 16 65,000 ± 4,000 5,100 ± 7,000 660 ± 50 61 ± 14 6.0 0.77
4-chloro COOCH3 H 25 ± 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
4.4 1.0
4-chloro methyl H 180 ± 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
2.0 1.6
4-chloro ethyl H 37 ± 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
9.7 9.1
4-chloro propyl H 11 ± 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
18.0 6.8
4-chloro isopropyl H 46 ± 16
900 ± 320
32 ± 6
990 ± 280
5,300 ± 1,300
>10 mM
3,300 ± 400
810 ± 170
>10 mM
51 ± 20
18.0 1.6
4-chloro butyl H 7.8 ± 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
29.0 3.2
4-chloro isobutyl H 16 ± 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
53.0 14.0
4-chloro pentyl H 23 ± 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
7.0 1.1
4-chloro isopentyl H 3.6 ± 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
230.0 15.0
4-chloro neopentyl H 120 ± 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
12.0 8.7
4-chloro cyclopentylmethyl H 9.4 ± 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
180.0 15.0
4-chloro cyclohexylmethyl H 130 ± 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
32.0 4.1
4-chloro benzyl H 440 ± 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
6.6 7.8
4-chloro phenethyl H 24 ± 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
75.0 4.3
4-chloro phenpropyl H 440 ± 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
1.1 2.1
4-chloro 3-pentyl H 400 ± 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
2.4 1.4
4-chloro cyclopentyl H 36 ± 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
11.0 1.6
3-chloro isobutyl H 3.7 ± 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
6.2 5.0
3,4-dichloro COOCH3 H 1.4 ± 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
10.0 0.43
3,4-dichloro propyl H 0.97 ± 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
4.0 1.8
3,4-dichloro butyl H 2.3 ± 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
5.2 4.7
3,4-dichloro isobutyl H 1.0 ± 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
25.0 1.6
3,4-dichloro isobutyl CH3 6.6 ± 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
29.0 2.2
4-methoxy isobutyl H 52 ± 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
60.0 16.0
3-methoxy isobutyl H 22 ± 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
170.0 9.4
4-isopropyl isobutyl H 3,300 ± 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
0.76 1.8
H COCH3 H 370 ± 70 190 ± 50 7,800 ± 1,200 >9,700 2,700 ± 400 220 ± 30 7.3 1.2
  • ɑ H = Equivalent overlay of structure sharing functional group
  • b CO2CH3 (i.e. COOCH3) = Equivalent overlay of structure sharing functional group
  • c CH3 = Equivalent overlay of structure sharing functional group
  • d possible 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 ± 11 1.03 ± 0.01 1,930 ± 360 0.82 ± 0.05 306 ± 13 1.12 ± 0.15 404 ± 26 2.0 12 0.16
Methylphenidate 74.6 ± 7.4 0.96 ± 0.08 270 ± 23 0.76 ± 0.06 14 ± 8%f 230 ± 16 >130 3.6 >47
3,4-dichloro-MPH 4.76 ± 0.62 2.07 ± 0.05 NDh 667 ± 83 1.07 ± 0.04 7.00 ± 140 140
6,610 ± 440 0.91 ± 0.01 11%b 3,550 ± 70 1.79 ± 0.55 8,490 ± 1,800 0.54 >0.76 <0.7
H 76.2 ± 3.4 1.05 ± 0.05 138 ± 9.0 1.12 ± 0.20 5,140 ± 670 1.29 ± 0.40 244 ± 2.5 67 1.8 37
3,4-diCl 3.39 ± 0.77 1.25 ± 0.29 28.4 ± 2.5 1.56 ± 0.80 121 ± 17 1.16 ± 0.31 11.0 ± 0.00 36 8.4 4.3
2-Cl 480 ± 46 1.00 ± 0.09 2,750; 58%b 0.96 1,840 ± 70 1.18 ± 0.06 1,260 ± 290 3.8 5.7 0.67
34.6 ± 7.6 0.95 ± 0.18 160 ± 18 1.28 ± 0.12 102 ± 8.2 1.01 ± 0.02 87.6 ± 0.35 3.0 4.6 0.64
CH2OH 2,100 ± 697 0.87 ± 0.09 NDh 16.2 ± 0.05%f 10,400 ± 530 >4.8
CH3 7,610 ± 800 1.02 ± 0.03 8.3%b 11 ± 5%f 7,960 ± 290 >1.3 ≫0.66
d R=OCH3, X=H 570 ± 49 0.94 ± 0.10 2,040; 64 ± 1.7%f 0.73 14 ± 3%f 1,850 ± 160 >18 3.6 >4.9
R=OH, X=H 6,250 ± 280 0.86 ± 0.03 23.7 ± 4.1%b 1 ± 1%f 10,700 ± 750 ≫1.6 >0.80
R=OH, X=3,4-diCl 35.7 ± 3.2 1.00 ± 0.09 367 ± 42 1.74 ± 0.87 2,050 ± 110 1.15 ± 0.12 NDh 57 10 5.6
H 908 ± 160 0.88 ± 0.05 4030; 52%b 1.04 5 ± 1%f 12,400 ± 1,500 ≫11 4.4 ≫2.5
3,4-diCl 14.0 ± 1.2 1.27 ± 0.20 280 ± 76 0.68 ± 0.09 54 ± 2%f NDh ~710 20 ~36
R=OH, X=H 108 ± 7.0 0.89 ± 0.10 351 ± 85 0.94 ± 0.27 12 ± 2%f 680 ± 52 >93 3.3 >28
R=OH, X=3,4-diCl 2.46 ± 0.52 1.39 ± 0.20 27.9 ± 3.5 0.70 ± 0.01 168 1.02 NDh 68 11 6.0
R=OCH3, X=H 10.8 ± 0.8 0.97 ± 0.07 63.7 ± 2.8 0.84 ± 0.04 2,070; 73 ± 5%f 0.90 61.0 ± 9.3 190 5.9 32
R1=CH3, R2=H 178 ± 28 1.23 ± 0.09 694 ± 65 0.88 ± 0.13 427 1.39 368 2.4 3.9 0.62
R1=H, R2=CH3 119 ± 20 1.17 ± 0.12 76.0 ± 12 0.88 ± 0.06 243 1.17 248 2.0 0.64 3.2
175 ± 8.0 1.00 ± 0.04 1,520 ± 120 0.97 ± 0.06 19 ± 4%f NDh >57 8.69 >6.6
R=CH2CH3, X=H 27.6 ± 1.7 1.29 ± 0.05 441 ± 49 1.16 ± 0.19 2,390; 80%f 1.12 NDh 87 15 5.8
R=CH2CH3, X=3,4-diCl 3.44 ± 0.02 1.90 ± 0.05 102 ± 19 1.27 ± 0.10 286 ± 47 1.30 ± 0.10 NDh 83 30 2.8
R=CH2CH3, X=H 5.51 ± 0.93 1.15 ± 0.03 60.8 ± 9.6 0.75 ± 0.07 3,550; 86%f 0.95 NDh 640 11 58
R=CH2CH3, X=3,4-diCl 4.12 ± 0.95 1.57 ± 0.00 98.8 ± 8.7 1.07 ± 0.07 199 ± 17 1.24 ± 0.00 NDh 48 24 2.0
6,360 ± 1,300 1.00 ± 0.04 36 ± 10%c 22 ± 7%f 8,800 ± 870 >1.6
i 4,560 ± 1,100 1.10 ± 0.09 534 ± 210c 0.96 ± 0.08 53 ± 6%f 1,060 ± 115 ~2.2 0.12 ~19
R1=CH2OH, R2=H, X=H 406 ± 4 1.07 ± 0.08 NDh 31.0 ± 1.5%f 1,520 ± 15 >25
R1=CH2OCH3, R2=H, X=H 89.9 ± 9.4 0.97 ± 0.04 NDh 47.8 ± 0.7%f 281 ± 19 ~110
R1=CH2OH, R2=H, X=3,4-diCl 3.91 ± 0.49 1.21 ± 0.06 NDh 276; 94.6%f 0.89 22.5 ± 1.4 71
R1=H, R2=CO2CH3, X=3,4-diCl 363 ± 20 1.17 ± 0.41 NDh 2,570 ± 580 1.00 ± 00.1 317 ± 46 7.1
R1=CO2CH3, R2=H, X=2-Cl 1,740 ± 200 0.98 ± 0.02 NDh 22.2 ± 2.5%f 2,660 ± 140 >5.7
  • ɑ Compounds tested as hydroclhoride (HCl) salts, unless otherwise noted.
  • b % inhibition caused by 5μM
  • c % inhibition caused by 10μM, as assayed by SRI
  • d Tested as free base
  • e Assayed by SRI (appropriate correction factor applied.)
  • f % inhibition of 10μM compound.
  • g Values expressed as x ± SEM of 2—5 replicate tests. (If no SEM shown, value is for an n of 1.)
  • h Not determined
  • i cf. 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
Methylphenidate 84 ± 33 153 ± 92 514 ± 74 >50,000
o-Bromomethylphenidate 880 ± 316 20,000
m-Bromomethylphenidate 4 ± 1 18 ± 11 20 ± 6 3,800
p-Bromomethylphenidate 21 ± 3 45 ± 19 31 ± 7 2,600
p-Hydroxymethylphenidate 125 263 ± 74 270 ± 69 17,000
p-Methyloxymethylphenidate 42 ± 24 490 ± 270 410 11,000
p-Nitromethylphenidate 180 360 5,900
p-Iodomethylphenidate 26 ± 14 32 1,800ɑ
m-Iodo-p-hydroxymethylphenidate 42 ± 21 195 ± 197 370 ± 64 5,900
N-Methylmethylphenidate 1,400 2,800 40,000
d-threo-Methylphenidate 33 244 ± 142 >50,000
l-threo-Methylphenidate 540 5,100 >50,000
dl-erythro-o-Bromomethylphenidate 10,000 50,000
Cocaine 120 313 ± 160 2,100 190
WIN 35,428 13 530 72
Nomifensine 29 ± 16 15 ± 2 1,300ɑ
Mazindol 9 ± 5 3 ± 2 92
Desipramine 1,400 3.5 200
Fluoxetine 3,300 3,400 2.4
  • ɑ Denotes 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

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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

Further reading