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.Klare H, Neudörfl JM, Brandt SD, Mischler E, Meier-Giebing S, Deluweit K, Westphal F, Laussmann T. Analysis of six 'neuro-enhancing' phenidate analogs. Drug Test Anal. 2017 Mar;9(3):423-435. Luethi D, Kaeser PJ, Brandt SD, Krähenbühl S, Hoener MC, Liechti ME. Pharmacological profile of methylphenidate-based designer drugs. Neuropharmacology. 2018 May 15;134(Pt A):133-140. Carlier J, Giorgetti R, Varì MR, Pirani F, Ricci G, Busardò FP. Use of cognitive enhancers: methylphenidate and analogs. Eur Rev Med Pharmacol Sci. 2019 Jan;23(1):3-15.
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
Structure Common name Chemical name CAS # 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 CTDP-32476 (2R)-2-[(1R)-1-(4-chlorophenyl)-3-methylbutyl]piperidine 928046-68-8 4-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 3-FPO 5-[(3-fluorophenyl)-piperidin-2-ylmethyl]-3-methyl-1,2,4-oxadiazole 3-fluorophenyl 3-methyl-1,2,4-oxadiazol-5-yl 4-FPO 5-[(4-fluorophenyl)-piperidin-2-ylmethyl]-3-methyl-1,2,4-oxadiazole 2743442-63-7 4-fluorophenyl 3-methyl-1,2,4-oxadiazol-5-yl 4-MPO 5-[(4-methylphenyl)-piperidin-2-ylmethyl]-3-methyl-1,2,4-oxadiazole 4-methylphenyl 3-methyl-1,2,4-oxadiazol-5-yl
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 # 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 HCl salt: [2731021-63-7] 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 Jongh David Karel De, Akkerman Antonie Marie, Kofman Hendrik,& Vries George De, (1961 to Nederlandsche Combinatie voor Chemische Industrie NV).Karel De Jongh David, et al. (1962 to Nederlandsche Combinatie voor Chemische Industrie NV). 2-Benzhydrylpiperazine
Isomerism
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 pKa) 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'salphanumericassignation(name) R1 R2 IC50 (nM)(Inhibition of [3H]WIN 35428 binding) IC50 (nM)(Inhibition of [3H]DA uptake) Selectivityuptake/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 ± 7.9224 ± 192.7 (R-benzoyl-methylecgonine)(cocaine) (H, H) 173 ± 13404 ± 262.3 351a (4F-MPH) F Hydrogeni.e.H 35.0 ± 3.0142 ± 2.04.1 351b Cl 20.6 ± 3.473.8 ± 8.13.6 351c Br 6.9 ± 0.126.3 ± 5.83.8 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 ± 0.164.5 ± 3.54.6 351g OH 98.0 ± 10340 ± 703.5 351h OCH3 83 ± 11293 ± 483.5 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 ± 1.2126 ± 13.8 351l t-Bu 13500 ± 4509350 ± 9500.7 351m NH2.HCl 34.6 ± 4.0115 ± 103.3 351n NO2 494 ± 331610 ± 2103.3 352a F 40.5 ± 4.5160 ± 0.004.0 352b Cl 5.1 ± 1.623.0 ± 3.04.5 352c Br 4.2 ± 0.212.8 ± 0.203.1 352d OH 321 ± 1.0790 ± 302.5 352e OMe 288 ± 53635 ± 350.2 352f Me 21.4 ± 1.1100 ± 184.7 352g NH2.HCl 265 ± 5578 ± 1602.2 353a 2-F 1420 ± 1202900 ± 3002.1 353b 2-Cl 1950 ± 2302660 ± 1401.4 353c 2-Br 1870 ± 1353410 ± 2901.8 353d 2-OH 23100 ± 5035,800 ± 8001.6 353e 2-OCH3 101,000 ± 10,00081,000 ± 20000.8 354a (3,4-DCMP) Cl, Cl(3,4-Cl2)5.3 ± 0.77.0 ± 0.61.3 354b I OH 42 ± 21195 ± 1974.6 354c OMe, OMe(3,4-OMe2)810 ± 101760 ± 1602.2
Aryl exchanged analogues