List of methylphenidate analogues

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.

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.

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

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. (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. This gives the potential to yield a conjugate salt form effectively protonated by a salt nearly chemically duplicate/identical to its own structure; creating a "methylphenidate ritalinate".

Receptor binding profiles of selected methylphenidate analogues

Aryl substitutions

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	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.

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

HDEP-28, Ethylnaphthidate.

Cycloalkane extensions, contractions & modified derivatives

Piperidine ring modified methylphenidate analogues

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.

Azido-iodo-N-benzyl analogues

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

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	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 K_i of (±)—threo-methylphenidate.
• ^b p <0.05 versus IC₅₀ of (±)—threo-methylphenidate.
• ^c p <0.05 versus its corresponding K_i.

Additional arene/nitrogen-linked MPH analogs

ChEMBL1254008

ChEMBL1255099

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 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 assays^g of rigid methylphenidate analogues

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.) 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.

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.

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

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.)

Further reading

• 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.
• 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.
• 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.
• Davies HM, Hopper DW, Hansen T, Liu Q, Childers SR (April 2004). "Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites". Bioorganic & Medicinal Chemistry Letters. 14 (7): 1799–802. doi:10.1016/j.bmcl.2003.12.097. PMID 15026075.
• Froimowitz M, Gu Y, Dakin LA, Kelley CJ, Parrish D, Deschamps JR (June 2005). "Vinylogous amide analogs of methylphenidate". Bioorganic & Medicinal Chemistry Letters. 15 (12): 3044–7. doi:10.1016/j.bmcl.2005.04.034. PMID 15908207.
• Schweri MM, Deutsch HM, Massey AT, Holtzman SG (May 2002). "Biochemical and behavioral characterization of novel methylphenidate analogs". The Journal of Pharmacology and Experimental Therapeutics. 301 (2): 527–35. doi:10.1124/jpet.301.2.527. PMID 11961053. S2CID 314970.
• Volz TJ, Bjorklund NL, Schenk JO (September 2005). "Methylphenidate analogs with behavioral differences interact differently with arginine residues on the dopamine transporter in rat striatum". Synapse. 57 (3): 175–8. doi:10.1002/syn.20161. PMID 15945061. S2CID 24352613.
• Lapinsky DJ, Yarravarapu N, Nolan TL, Surratt CK, Lever JR, Tomlinson M, et al. (May 2012). "Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate". ACS Medicinal Chemistry Letters. 3 (5): 378–382. doi:10.1021/ml3000098. PMC 3469269. PMID 23066448.
• Deutsch HM, Ye X, Shi Q, Liu Z, Schweri MM (April 2001). "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. doi:10.1016/s0223-5234(01)01230-2. PMID 11461755.