List of methylphenidate analogues

3D molecular rendering of methylphenidate (MPH)

File:Ethylphenidate 3d spin.gif

3D molecular rendering of ethylphenidate (EPH)

This is a list of methylphenidate (MPH or MPD) analogues. Regular methylphenidate can come in several varieties. Including: 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 which has a binding profile on par with or better than that of cocaine. (Note however the measure of five fold (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 conformation 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".

The carboxymethyl (methyl acetate) has sometimes been replaced with similar length ketones to increase duration. For instance, the methoxycarbonyl has had examples of having been replaced with an alkyl group (such as Kozikowski showed with RTI-31 n-propyl residue. cf.)

Desoxypipradrol (and thus Pipradrol, including such derivatives as AL-1095, Diphemethoxidine, SCH-5472 & D2PM), and even mefloquine, 2-benzylpiperidine & rimiterol could be considered vaguely related structurally, with the former ones also functionally so, as loosely analogous compounds.

Enpiroline is one further example, loosely related by being based on the 2-benzylpiperidine skeleton, although in its case it is actually heteroaromatic; also of note are etoxadrol and dioxadrol.

Pethidine (Meperidine) is a loose structural analog (being rather between methylphenidate and certain piperidine phenyltropanes) which, though considered functionally an opioid, is also shown to have dopaminergic reuptake qualities.

Common (e.g. well established in literature et attested within grey market depositories) MPH analog compounds

• 

  Racemic methylphenidate

• 

  Enantiopure dextrorotatory
  ("D")methylphenidate
  (The stereochemistry on both carbons is dictated by 1 single wedge)
  e.g. Focalin

• 

  Transesterification product of MPH
  when exposed to ethanol in vivo

• 

  4-MeTMP

• 

  Propylphenidate

• 

  Dichloro-methylphenidate

• 

  Methylnaphthidate^{✲
  ✲}The aforementioned specific analogue page has an additional binding values table at its remote internal-link for multiple threo-methylphenidate analogues besides its own.

• 

  O-2172 The usual methylphenidate piperidine ring has been replaced by a cyclopentane (without the pyrrolidine nitrogen) and a di-chloro at the phenyl ring

• 

  Isopropylphenidate

• MPH-RRA.png

  Restricted Rotation Analog (RRA)
  of threo-methylphenidate.
  (cf. vabicaserin)

Staple permutations of ubiquitous simple substitution pattern arrangements of methylphenidate

The differing combinations of R/S-(+)- isomers of Ethylphenidate^* (EPH)

220px

(R,R)-(+)- isomer ^{vide supra}

220px

(R,S)-(+)- isomer ^{vide supra}

220px

(S,R)-(+)- isomer ^{vide supra}

220px

(S,S)-(+)- isomer ^{vide supra}

^*Aforementioned as possible "trans-esterification" product of MPH:
^{Note carboxy has ethyl (i.e. carbethoxy) rather than methyl (i.e. carbmethoxy)}

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
x180px
	351a	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	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
x180px
	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
x180px	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
x180px	354a	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

File:Cyclo-Methiodrone.png

Piperidin-2-yl(thiophen-2-yl)methanone or cyclomethiodrone (TCAT), an empathogen methylphenidate analogue.

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).

Pentedrone is a structure similar to the above TCAT, yet is an intermediate between the methylphenidate class and that of the substituted cathinones.

e.g. out from among such examples, the differentiating factor is that the ring formation is left open ("opened" with the excess bond not fused, as above, or omitting one or more bonds on the ring: such as is the case with MABP) in the non-MPH compared analogues.

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
x150px	374	1-naphthalene	194 ± 15	1981 ± 443	10.2
	375 (HDMP-28)	2-naphthalene	79.5	85.2 ± 25	1.0
x180px	376	benzyl	>5000	-	-

File:HDMP-29.svg

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)
x150px
	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)
x150px	380	2-pyrrolidine (cyclopentane)	1336 ± 108
x150px	381	2-azepane (cycloheptane)	1765 ± 113
x150px	382	2-azocane (cyclooctane)	3321 ± 551
x150px	383	4-1,3-oxazinane (cyclohexane)	6689 ± 1348

x170px Methyl 2-(1,2-oxazinan-3-yl)-2-phenylacetate

x170px Methyl 2-(1,3-oxazinan-2-yl)-2-phenylacetate

☝The two other (in addition to compound 383) potential oxazinane methylphenidate analogues.

x170px Methyl 2-phenyl-2-(morpholin-3-yl)acetate A.K.A. Methyl 2-morpholin-3-yl-2-phenylacetate

☜Methylmorphenate methylphenidate analogue.

File:FlexedRingD-Threo-Methylphenidate.svg

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.

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

• ^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.

Test environment conditioning & control studies

Temperature effect with Hill slope measurements on MPD binding IC₅₀ (nM) values for MAT.

Compound	0° (zero degrees)	0° (zero degrees) Hill slopeɑ	22° (twenty-two degrees)	22° (twenty-two degrees) Hill slopeɑ	36° (thirty-six degrees)	36° (thirty-six degrees) Hill slopeɑ
Methylphenidate (MPH, MPD)	51 ± 24	0.99 ± 0.11	72 ± 29	0.90 ± 0.10	265 ± 175	0.70 ± 0.02
o-bromo-methylphenidate	1150 ± 83	0.97 ± 0.08	880 ± 316	0.79 ± 0.14	954 ± 190	0.88 ± 0.08

• ^ɑThe 'Hill' "slope" is a parameter for a biochemical equation named for Archibald Hill; 'degrees' in all cases refer to temperature, measurement of heat & cold, and not to angles. Thus "Hill slope" terminology herein has naught to do with effect of g-force or deviations of a level plane in the context of these values.

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 phenyltropanes
• List of cocaine analogues
• Substituted phenylmorpholines

External links

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.)

• "Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters." doi:10.1016/0024-3205(96)00052-5 Mirror hotlink
• "Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling." Bioorg Med Chem. 2011 Jan 1;19(1):504-12. doi: 10.1016/j.bmc.2010.11.002. Epub 2010 Nov 4.
• "Uses of methylphenidate derivatives" Google patents. Pub. # US 20060183773 A1
• Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007 Jan 25;50(2):219-32.
• Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites. doi:10.1016/j.bmcl.2003.12.097
• Vinylogous amide analogs of methylphenidate. Bioorg Med Chem Lett. 2005 Jun 15;15(12):3044-7.
• Biochemical and Behavioral Characterization of Novel Methylphenidate Analogs doi: 10.1124/jpet.301.2.527
• Methylphenidate analogs with behavioral differences interact differently with arginine residues on the dopamine transporter in rat striatum doi: 10.1002/syn.20161
• Quantitative structure-activity relationship studies of threo-methylphenidate analogs.
• Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate doi: 10.1021/ml3000098
• 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. Howard M Deutsch et al. Volume 36, Issue 4, April 2001, Pages 303–311