List of methylphenidate analogues explained

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).

Notable phenidate derivatives

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
		4-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 compoundsA 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
		(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

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. (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.) Furthermore, the energy to change between its two rotamers involves the stabilizing of the hydrogen bond between the protonated amine (of an 8.5 pK_a) 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.

Also of note is that methylphenidate in demethylated form is acidic; a metabolite (and precursor) known as ritalinic acid.^[6] This gives the potential to yield a conjugate salt^[7] form effectively protonated by a salt nearly chemically duplicate/identical to its own structure; creating a "methylphenidate ritalinate".^[8]

Receptor binding profiles of selected methylphenidate analogues

Aryl substitutions

Phenyl ring substituted methylphenidate analogues! 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).

Aryl exchanged analogues

Phenyl ring modified methylphenidate analogues! Compound! S. Singh's
alphanumeric
assignation
(name)! Ring! K_i (nM)
(Inhibition of [¹²⁵I]IPT binding)! K_i (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	-	-

Piperidine nitrogen methylated phenyl-substituted variants

N-methyl phenyl ring substituted methylphenidate analogues! 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

Cycloalkane extensions, contractions & modified derivatives

Piperidine ring modified methylphenidate analogues! Compound! S. Singh's
alphanumeric
assignation
(name)! Cycloalkane
ring! K_i (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-phenyl-2-(morpholin-3-yl)acetate A.K.A. Methyl 2-morpholin-3-yl-2-phenylacetate

☜Methylmorphenate methylphenidate analogue.^[9]

Azido-iodo-N-benzyl analogues

Structures of Azido-iodo-N-benzyl analogues of methylphenidate with affinities.^[10]

Azido-iodo-N-benzyl methylphenidate analogs inhibitition of [³H]WIN 35428 binding and [³H]dopamine uptake at hDAT N2A neuroblastoma cells.
(Each K_i 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! K_i (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 ± 3^ɑ	11 ± 2^b
	(±)—3-I-methylphenidate	meta-iodo	H	4.5 ± 1^ɑ	14 ± 5^b
	(±)—p-N3-N-Bn-4-I-methylphenidate	para-iodo	para-N3-N-Benzyl	363 ± 28^ɑ	2764 ± 196^bc
	(±)—m-N3-N-Bn-4-I-methylphenidate	para-iodo	meta-N3-N-Benzyl	2754 ± 169^ɑ	7966 ± 348^bc
	(±)—o-N3-N-Bn-4-I-methylphenidate	para-iodo	ortho-N3-N-Benzyl	517 ± 65^ɑ	1232 ± 70^bc
	(±)—p-N3-N-Bn-3-I-methylphenidate	meta-iodo	para-N3-N-Benzyl	658 ± 70^ɑ	1828 ± 261^bc
	(±)—m-N3-N-Bn-3-I-methylphenidate	meta-iodo	meta-N3-N-Benzyl	2056 ± 73^ɑ	4627 ± 238^bc
	(±)—o-N3-N-Bn-3-I-methylphenidate	meta-iodo	ortho-N3-N-Benzyl	1112 ± 163^ɑ	2696 ± 178^bc
	(±)—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 K_i of (±)—threo-methylphenidate.
• ^b p <0.05 versus IC₅₀ of (±)—threo-methylphenidate.
• ^c p <0.05 versus its corresponding K_i.

Alkyl substituted-carbomethoxy analogues

Alkyl RR/SS diastereomer analogs of methylphenidate
(RS/SR diastereomer values of otherwise same compounds given in small grey typeface)! Structure! R¹! R²! R³! Dopamine transporter K_i (nM)
(Inhibition of [I¹²⁵H]RTI-55 binding)! DA uptake
IC₅₀ (nM)! Serotonin transporter K_i (nM)
(Inhibition of [I¹²⁵H]RTI-55 binding)! 5HT uptake
IC₅₀ (nM)! Norepinephrine transporter K_i (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 ± 900^d

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 assays^g of rigid methylphenidate analogues^[11] ! Compound^ɑ! R & X substitution(s)! K_i (nM)
@ DAT with [³3]WIN 35,065-2! n_H
@ DAT with [³3]WIN 35,065-2! K_i (nM) or
% inhibition
@ NET with [³3]Nisoxetine! n_H
@ NET with [³3]Nisoxetine! K_i (nM) or
% inhibition
@ 5-HTT with [³3]Citalopram! n_H
@ 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

ND^h

—

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

ND^h

—

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

ND^h

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

—

ND^h

~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

ND^h

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

—

ND^h

>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

ND^h

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

ND^h

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

ND^h

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

ND^h

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 ± 210^c

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

ND^h

—

31.0 ± 1.5%^f

—

1,520 ± 15

>25

—

—

R1=CH2OCH3, R2=H, X=H

89.9 ± 9.4

0.97 ± 0.04

ND^h

—

47.8 ± 0.7%^f

—

281 ± 19

~110

—

—

R1=CH2OH, R2=H, X=3,4-diCl

3.91 ± 0.49

1.21 ± 0.06

ND^h

—

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

ND^h

—

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

ND^h

—

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

Various MPH congener affinity values inclusive of norepinephrine & serotonin

Values for dl-threo-methylphenidate derivatives are the mean (s.d.)^[12] 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.^[13]

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	1,800^ɑ
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
	13	—	530	72
	29 ± 16	—	15 ± 2	1,300^ɑ
	9 ± 5	—	3 ± 2	92
	1,400	—	3.5	200
	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

• List of modafinil analogues
• List of cocaine analogues
• Substituted cathinone

Further reading

• Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS . Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters . Life Sciences . 58 . 12 . 231–9 . 1996 . 8786705 . 10.1016/0024-3205(96)00052-5 .
• Lapinsky DJ, Velagaleti R, Yarravarapu N, Liu Y, Huang Y, Surratt CK, Lever JR, Foster JD, Acharya R, Vaughan RA, Deutsch HM . 6 . 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 . January 2011 . 21129986 . 3023924 . 10.1016/j.bmc.2010.11.002 .
• Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A . 6 . Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter . Journal of Medicinal Chemistry . 50 . 2 . 219–32 . January 2007 . 17228864 . 10.1021/jm0608614 .
• Davies HM, Hopper DW, Hansen T, Liu Q, Childers SR . Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites . Bioorganic & Medicinal Chemistry Letters . 14 . 7 . 1799–802 . April 2004 . 15026075 . 10.1016/j.bmcl.2003.12.097 .
• Froimowitz M, Gu Y, Dakin LA, Kelley CJ, Parrish D, Deschamps JR . Vinylogous amide analogs of methylphenidate . Bioorganic & Medicinal Chemistry Letters . 15 . 12 . 3044–7 . June 2005 . 15908207 . 10.1016/j.bmcl.2005.04.034 .
• Schweri MM, Deutsch HM, Massey AT, Holtzman SG . Biochemical and behavioral characterization of novel methylphenidate analogs . The Journal of Pharmacology and Experimental Therapeutics . 301 . 2 . 527–35 . May 2002 . 11961053 . 10.1124/jpet.301.2.527 . 314970 .
• Volz TJ, Bjorklund NL, Schenk JO . Methylphenidate analogs with behavioral differences interact differently with arginine residues on the dopamine transporter in rat striatum . Synapse . 57 . 3 . 175–8 . September 2005 . 15945061 . 10.1002/syn.20161 . 24352613 .
• Lapinsky DJ, Yarravarapu N, Nolan TL, Surratt CK, Lever JR, Tomlinson M, Vaughan RA, Deutsch HM . 6 . Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate . ACS Medicinal Chemistry Letters . 3 . 5 . 378–382 . May 2012 . 23066448 . 3469269 . 10.1021/ml3000098 .
• Deutsch HM, Ye X, Shi Q, Liu Z, Schweri MM . Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction . European Journal of Medicinal Chemistry . 36 . 4 . 303–11 . April 2001 . 11461755 . 10.1016/s0223-5234(01)01230-2 .

Notes and 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, Westphal F, Laussmann T . 6 . Analysis of six 'neuro-enhancing' phenidate analogs . Drug Testing and Analysis . 9 . 3 . 423–435 . March 2017 . 28067464 . 10.1002/dta.2161 .
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 . Pharmacological profile of methylphenidate-based designer drugs . Neuropharmacology . 134 . Pt A . 133–140 . May 2018 . 28823611 . 10.1016/j.neuropharm.2017.08.020 . 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 . Use of cognitive enhancers: methylphenidate and analogs . European Review for Medical and Pharmacological Sciences . 23 . 1 . 3–15 . January 2019 . 30657540 . 10.26355/eurrev_201901_16741 . 58643522 .
4. Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A . 6 . Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter . Journal of Medicinal Chemistry . 50 . 2 . 219–32 . January 2007 . 17228864 . 10.1021/jm0608614 .
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 . 10.1016/j.bmc.2010.08.034 . 20846865 .
6. Marchei E, Farré M, Pardo R, Garcia-Algar O, Pellegrini M, Pacifici R, Pichini S . Correlation between methylphenidate and ritalinic acid concentrations in oral fluid and plasma . Clinical Chemistry . 56 . 4 . 585–92 . April 2010 . 20167695 . 10.1373/clinchem.2009.138396 . free .
7. Gutman A, Zaltsman I, Shalimov A, Sotrihin M, Nisnevich G, Yudovich L, Fedotev I . Process for the preparation of dexmethylphenidate hydrochloride . US . 20040180928 . 16 September 2004 . ISP Investments LLC .
8. Shahriari H, Gerard Z, Potter A . Resolution of ritalinic acid salt . US . 6441178 . Medeva Europe Ltd . 27 August 2002 .
9. Web site: U.S. National Library of Medicine . Compound Summary for CID 85054562 . PubChem .
10. Lapinsky DJ, Velagaleti R, Yarravarapu N, Liu Y, Huang Y, Surratt CK, Lever JR, Foster JD, Acharya R, Vaughan RA, Deutsch HM . 6 . 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 . January 2011 . 21129986 . 3023924 . 10.1016/j.bmc.2010.11.002 .
11. Kim DI, Deutsch HM, Ye X, Schweri MM . Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate . Journal of Medicinal Chemistry . 50 . 11 . 2718–31 . May 2007 . 17489581 . 10.1021/jm061354p .
12. Jaykaran . "Mean ± SEM" or "Mean (SD)"? . Indian Journal of Pharmacology . 42 . 5 . 329 . October 2010 . 21206631 . 2959222 . 10.4103/0253-7613.70402 . free .
13. Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS . Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters . Life Sciences . 58 . 12 . 231–9 . 1996 . 8786705 . 10.1016/0024-3205(96)00052-5 .