List of methylphenidate analogues

3D molecular rendering of methylphenidate (MPH)

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.^{[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 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.^[5] 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.^[6])

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.^[7]

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^[8]
• 
  Restricted Rotation Analog (RRA)
  of threo-methylphenidate.^[9]
  (i.e. quinolizidines, cf. vabicaserin)

Staple permutations of ubiquitous simple substitution pattern arrangements of methylphenidate

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

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

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

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

(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^{[lower-alpha 4]}

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	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	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	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

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).^{[lower-alpha 5]}

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^{[lower-alpha 6]}

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.^[10]

Piperidine nitrogen methylated phenyl-substituted variants

N-methyl phenyl ring substituted methylphenidate analogues^{[lower-alpha 7]}

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^{[lower-alpha 8]}

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.[11]

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.

Azido-iodo-N-benzyl analogues

Structures of Azido-iodo-N-benzyl analogues of methylphenidate with affinities.^[12]

Azido-iodo-N-benzyl methylphenidate analogs inhibitition of [³H]WIN 35428 binding and [³H]dopamine uptake at hDAT N2A neuroblastoma cells.^[12]
(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	—	—

• ^ɑp <0.05 versus K_i of (±)—threo-methylphenidate.
• ^bp <0.05 versus IC₅₀ of (±)—threo-methylphenidate.
• ^cp <0.05 versus its corresponding K_i.

Additional arene/nitrogen-linked MPH analogs

ChEMBL1254008^[13]

ChEMBL1255099^[14]

Alkyl substituted-carbmethoxy analogues

Alkyl RR/SS diastereomer analogs of methylphenidate^[5]
(RS/SR diastereomer values of otherwise same compounds given in small grey typeface^[5])

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

• ^ɑH = Equivalent overlay of structure sharing functional group
• ^bCO₂CH₃ (i.e. COOCH₃) = Equivalent overlay of structure sharing functional group
• ^cCH₃ = Equivalent overlay of structure sharing functional group
• ^dpossible 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^[9]

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	—	—

Bisphenol A (BPA): Shown to mimic estrogenic activity to affect various dopaminergic processes, enhancing mesolimbic dopamine activity & conferring resultant stimulation.^[15]

• ^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

Various MPH congener affinity values inclusive of norepinephrine & serotonin

Values for dl-threo-methylphenidate derivatives are the mean (s.d.)^[16] 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.^[17]

• ^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

• ^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 modafinil analogues
• List of cocaine analogues
• List of phenyltropanes

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.)

• Gatley, SJ; Pan, D; Chen, R; Chaturvedi, G; Ding, YS (1996). "Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters". Life Sci. 58: 231–9. PMID 8786705. 
• Lapinsky, DJ; Velagaleti, R; Yarravarapu, N; Liu, Y; Huang, Y; Surratt, CK; Lever, JR; Foster, JD; Acharya, R; Vaughan, RA; Deutsch, HM. "Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling". Bioorg Med Chem. 19: 504–12. PMC 3023924 . PMID 21129986. doi:10.1016/j.bmc.2010.11.002. 
• "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: 219–32. PMID 17228864. doi:10.1021/jm0608614. CS1 maint: Explicit use of et al. (link)
• 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: 1799–1802. PMID 15026075. doi:10.1016/j.bmcl.2003.12.097. 
• Froimowitz, M; Gu, Y; Dakin, LA; Kelley, CJ; Parrish, D; Deschamps, JR. "Vinylogous amide analogs of methylphenidate". Bioorg Med Chem Lett. 15: 3044–7. PMID 15908207. doi:10.1016/j.bmcl.2005.04.034. 
• 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: 527–535. PMID 11961053. doi:10.1124/jpet.301.2.527. 
• "Methylphenidate analogs with behavioral differences interact differently with arginine residues on the dopamine transporter in rat striatum". Synapse. 57: 175–178. doi:10.1002/syn.20161. 
• Quantitative structure-activity relationship studies of threo-methylphenidate analogs.
• Lapinsky, DJ; Yarravarapu, N; Nolan, TL; Surratt, CK; Lever, JR; Tomlinson, M; Vaughan, RA; Deutsch, HM. "Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate". ACS Med Chem Lett. 3: 378–382. PMC 3469269 . PMID 23066448. 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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