List of methylphenidate analogues

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
		Phenidate			phenyl	COOH
	2-BZPD	2-Benzylpiperidine	32838-55-4	phenyl	H
	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
	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		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-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		naphthalen-2-yl	COOEt
	MTMP	Methyl (thiophen-2-yl)(piperidin-2-yl)acetate		thiophen-2-yl	COOMe
	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
	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

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 1] (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 2]) 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.[lower-alpha 3]

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]

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[14]

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	—	—

• ^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

Values for dl-threo-methylphenidate derivatives are the mean (s.d.)[15] 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.[16]

• ^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.

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.)

• Gatley, SJ; Pan, D; Chen, R; Chaturvedi, G; Ding, YS (1996). "Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters". Life Sci. 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; Lever, JR; Foster, JD; Acharya, R; Vaughan, RA; Deutsch, HM (2011). "Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling". Bioorg Med Chem. 19 (1): 504–12. doi:10.1016/j.bmc.2010.11.002. PMC 3023924. PMID 21129986.
• "Uses of methylphenidate derivatives" Google patents. Pub. # US 20060183773 A1
• Froimowitz, M; Gu, Y; Dakin, LA; et al. (January 2007). "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". J. Med. Chem. 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. 14 (7): 1799–1802. doi:10.1016/j.bmcl.2003.12.097. PMID 15026075.
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• Schweri, MM; Deutsch, HM; Massey, AT; Holtzman, SG (May 2002). "Biochemical and Behavioral Characterization of Novel Methylphenidate Analogs". Journal of Pharmacology and Experimental Therapeutics. 301 (2): 527–535. doi:10.1124/jpet.301.2.527. PMID 11961053.
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• Lapinsky, DJ; Yarravarapu, N; Nolan, TL; Surratt, CK; Lever, JR; Tomlinson, M; Vaughan, RA; Deutsch, HM (2012). "Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate". ACS Med Chem Lett. 3 (5): 378–382. doi:10.1021/ml3000098. PMC 3469269. PMID 23066448.
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