List of methylphenidate analogues

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 & lastly the isomers S,S; S,R/R,S or R,R. 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. Which has a binding profile on par with or better than that of cocaine.^{[lower-alpha 1]}

Also of note is that methylphenidate in demethylated form is acidic; a conformation known as ritalinic acid.^[2] This gives the potential to yield a conjugate salt^[3] form effectively protonated by a salt nearly chemically duplicate/identical to its own structure; creating a "methylphenidate ritalinate".^[4]

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. c.f.^[5])

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

Table of methylphenidate variants: click to

Racemic methylphenidate Enantiopure dextrorotatory ("D")methylphenidate Transesterification product of MPH when exposed to ethanol in vivo 4-MeTMP Propylphenidate Dichloro-methylphenidate Methylnaphthidate O-2172: the usual methylphenidate piperidine ring has been replaced by a cyclopentane (without the pyrrolidine nitrogen) and a di-chloro at the phenyl ring Isopropylphenidate[6][7] Restricted Rotation Analog (RRA) of threo-methylphenidate.

Phenyl ring substituted methylphenidate analogues^{[lower-alpha 2]}

Compound	S. Singh's alphanumeric assignation (name)	R	R′	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	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
	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	F		1420 ± 120	2900 ± 300	2.1
	353b	Cl		1950 ± 230	2660 ± 140	1.4
	353c	Br		1870 ± 135	3410 ± 290	1.8
	353d	OH		23100 ± 50	35,800 ± 800	1.6
	353e	OCH3		101,000 ± 10,000	81,000 ± 2000	0.8
	354a	Cl, Cl		5.3 ± 0.7	7.0 ± 0.6	1.3
	354b	I	OH	42 ± 21	195 ± 197	4.6
	354c	OMe, OMe		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).^{[lower-alpha 3]}

Phenyl ring modified methylphenidate analogues^{[lower-alpha 4]}

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.^[8]

N-methyl phenyl ring substituted methylphenidate analogues^{[lower-alpha 5]}

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

Piperidine ring modified methylphenidate analogues^{[lower-alpha 6]}

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

Alternate two dimensional rendering of "D-threo-methylphenidate"; demonstrating the plasticity of the piperidine ring in a 'flexed' conformation.

See also

• List of phenyltropanes
• List of cocaine analogues

External links

• "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

References

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