list of methylphenidate analogues list of methylphenidate analogues 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. 3d molecular rendering of methylphenidate (mph) 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 & methylphenidate being —25.5 kcal/mol (δs°, measured using gbr 1278 @ 25 °c) notable phenidate derivatives 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 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) methyl] acetate 24558-01-8 phenyl ocome rimiterol 4-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 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-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 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-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 isomerism 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. (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 win 35428 binding) ic50 (nm)(inhibition of da uptake) selectivityuptake/binding (d-threo-methylphenidate)h, h33244 ± 142(171 ± 10)7.4 (l-threo-methylphenidate)5405100(1468 ± 112)9.4 (d/l-threo-methylphenidate)"eudismic ratio"6.420.9(8.6)- (dl-threo-methylphenidate)83.0 ± 7.9224 ± 192.7 (r-benzoyl-methylecgonine)(cocaine)(h, h)173 ± 13404 ± 262.3 351a (4f-mph)fhydrogeni.e.h35.0 ± 3.0142 ± 2.04.1 351bcl20.6 ± 3.473.8 ± 8.13.6 351cbr6.9 ± 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- 351fi14.0 ± 0.164.5 ± 3.54.6 351goh98.0 ± 10340 ± 703.5 351hoch383 ± 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)ch333.0 ± 1.2126 ± 13.8 351lt-bu13500 ± 4509350 ± 9500.7 351mnh2.hcl34.6 ± 4.0115 ± 103.3 351nno2494 ± 331610 ± 2103.3 352af40.5 ± 4.5160 ± 0.004.0 352bcl5.1 ± 1.623.0 ± 3.04.5 352cbr4.2 ± 0.212.8 ± 0.203.1 352doh321 ± 1.0790 ± 302.5 352eome288 ± 53635 ± 350.2 352fme21.4 ± 1.1100 ± 184.7 352gnh2.hcl265 ± 5578 ± 1602.2 353a2′-f1420 ± 1202900 ± 3002.1 353b2′-cl1950 ± 2302660 ± 1401.4 353c2′-br1870 ± 1353410 ± 2901.8 353d2′-oh23100 ± 5035,800 ± 8001.6 353e2′-och3101,000 ± 10,00081,000 ± 20000.8 354a (3,4-dcmp)cl, cl(3′,4′-cl2)5.3 ± 0.77.0 ± 0.61.3 354bioh42 ± 21195 ± 1974.6 354come, ome(3′,4′-ome2)810 ± 101760 ± 1602.2 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). aryl exchanged analogues phenyl ring modified methylphenidate analogues compound s. singh'salphanumericassignation(name) ring ki (nm)(inhibition of ipt binding) ki (nm)(inhibition of da uptake) selectivityuptake/binding (d-threo-methylphenidate)benzene324-- (dl-threo-methylphenidate)82 ± 77429 ± 880.7 3741-naphthalene194 ± 151981 ± 44310.2 375(hdmp-28)2-naphthalene79.585.2 ± 251.0 376benzyl>5000-- 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'salphanumericassignation(name) r ic50 (nm)(inhibition of binding at dat) 373ah500 ± 25 373b4″-oh1220 ± 140 373c4″-ch3139 ± 13 373d3″-cl161 ± 18 373e3″-me108 ± 16 hdep-28, ethylnaphthidate. cycloalkane extensions, contractions & modified derivatives piperidine ring modified methylphenidate analogues compound s. singh'salphanumericassignation(name) cycloalkane ring ki (nm)(inhibition of binding) 3802-pyrrolidine(cyclopentane)1336 ± 108 3812-azepane(cycloheptane)1765 ± 113 3822-azocane(cyclooctane)3321 ± 551 3834-1,3-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)acetatea.k.a. methyl 2-morpholin-3-yl-2-phenylacetate☜methylmorphenate methylphenidate analogue. azido-iodo-n-benzyl analogues structures of azido-iodo-n-benzyl analogues of methylphenidate with affinities. azido-iodo-n-benzyl methylphenidate analogs inhibitition of win 35428 binding and dopamine uptake at hdat n2a neuroblastoma cells.(each ki 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 win 35428 binding) ic50 (nm)(inhibition of da uptake) (±)—threo-methylphenidatehh25 ± 1156 ± 58 (±)—4-i-methylphenidatepara-iodoh14 ± 3ɑ11 ± 2b (±)—3-i-methylphenidatemeta-iodoh4.5 ± 1ɑ14 ± 5b (±)—p-n3-n-bn-4-i-methylphenidatepara-iodopara-n3-n-benzyl363 ± 28ɑ2764 ± 196bc (±)—m-n3-n-bn-4-i-methylphenidatepara-iodometa-n3-n-benzyl2754 ± 169ɑ7966 ± 348bc (±)—o-n3-n-bn-4-i-methylphenidatepara-iodoortho-n3-n-benzyl517 ± 65ɑ1232 ± 70bc (±)—p-n3-n-bn-3-i-methylphenidatemeta-iodopara-n3-n-benzyl658 ± 70ɑ1828 ± 261bc (±)—m-n3-n-bn-3-i-methylphenidatemeta-iodometa-n3-n-benzyl2056 ± 73ɑ4627 ± 238bc (±)—o-n3-n-bn-3-i-methylphenidatemeta-iodoortho-n3-n-benzyl1112 ± 163ɑ2696 ± 178bc (±)—n-bn-methylphenidatehn-benzyl—— (±)—n-bn-3-chloro-methylphenidate3-cln-benzyl—— (±)—n-bn-3,4-dichloro-methylphenidate3,4-dicln-benzyl—— (±)—p-chloro-n-bn-methylphenidatehpara-cl-n-benzyl—— (±)—p-methoxy-n-bn-methylphenidatehpara-ome-n-benzyl—— (±)—m-chloro-n-bn-methylphenidatehmeta-cl-n-benzyl—— (±)—p-nitro-n-bn-methylphenidatehpara-no2-n-benzyl—— ɑp <0.05 versus ki of (±)—threo-methylphenidate. bp <0.05 versus ic50 of (±)—threo-methylphenidate. cp <0.05 versus its corresponding ki. additional arene/nitrogen-linked mph analogschembl1254008chembl1255099 alkyl substituted-carbomethoxy analogues alkyl rr/ss diastereomer analogs of methylphenidate(rs/sr diastereomer values of otherwise same compounds given in small grey typeface) structure r1 r2 r3 dopamine transporter ki (nm)(inhibition of rti-55 binding) da uptakeic50 (nm) serotonin transporter ki (nm)(inhibition of rti-55 binding) 5ht uptakeic50 (nm) norepinephrine transporter ki (nm)(inhibition of rti-55 binding) ne uptakeic50 (nm) ne/da selectivity(binding displacement) ne/da selectivity(uptake blocking) cocaine—ɑ—b—c500 ± 65240 ± 15340 ± 40250 ± 40500 ± 90210 ± 301.00.88 hcooch3h110 ± 979 ± 1665,000 ± 4,0005,100 ± 7,000660 ± 5061 ± 146.00.77 4-chlorocooch3h25 ± 82,000 ± 60011 ± 282,700 ± 1,0006,000 ± 1005,900 ± 200>9,800>10 mm110 ± 40>6,10011 ± 31,400 ± 4004.41.0 4-chloromethylh180 ± 70>3,90022 ± 71,500 ± 7004,900 ± 500>9,1001,900 ± 3004,700 ± 800360 ± 140>6,30035 ± 133,200 ± 8002.01.6 4-chloroethylh37 ± 101,800 ± 30023 ± 52,800 ± 7007,800 ± 8004,200 ± 4002,400 ± 4004,100 ± 1,000360 ± 60>9,200210 ± 301,300 ± 4009.79.1 4-chloropropylh11 ± 3380 ± 407.4 ± 0.4450 ± 602,700 ± 6003,200 ± 1,1002,900 ± 1,1001,300 ± 7200 ± 801,400 ± 40050 ± 15200 ± 5018.06.8 4-chloroisopropylh46 ± 16900 ± 32032 ± 6990 ± 2805,300 ± 1,300>10 mm3,300 ± 400—810 ± 170>10 mm51 ± 20—18.01.6 4-chlorobutylh7.8 ± 1.1290 ± 708.2 ± 2.1170 ± 404,300 ± 4004,800 ± 7004,000 ± 4003,300 ± 600230 ± 301,600 ± 30026 ± 7180 ± 6029.03.2 4-chloroisobutylh16 ± 4170 ± 508.6 ± 2.9380 ± 1305,900 ± 9004,300 ± 500490 ± 80540 ± 150840 ± 1304,500 ± 1,500120 ± 40750 ± 17053.014.0 4-chloropentylh23 ± 7870 ± 14045 ± 14650 ± 202,200 ± 1003,600 ± 1,0001,500 ± 3001,700 ± 700160 ± 401,500 ± 30049 ± 16860 ± 3307.01.1 4-chloroisopentylh3.6 ± 1.2510 ± 17014 ± 2680 ± 1205,000 ± 4706,700 ± 5007,300 ± 1,400>8,300830 ± 11012,000 ± 1,400210 ± 403,000 ± 540230.015.0 4-chloroneopentylh120 ± 40600 ± 4060 ± 2670 ± 2603,900 ± 5003,500 ± 1,000>8,3001,800 ± 6001,400 ± 400>5,500520 ± 110730 ± 25012.08.7 4-chlorocyclopentylmethylh9.4 ± 1.5310 ± 8021 ± 1180 ± 202,900 ± 803,200 ± 7002,100 ± 9005,600 ± 1,4001,700 ± 6002,600 ± 800310 ± 40730 ± 230180.015.0 4-chlorocyclohexylmethylh130 ± 40260 ± 30230 ± 70410 ± 60900 ± 4003,700 ± 5001,000 ± 2006,400 ± 1,3004,200 ± 2004,300 ± 200940 ± 1401,700 ± 60032.04.1 4-chlorobenzylh440 ± 110550 ± 60370 ± 90390 ± 601,100 ± 2004,300 ± 8001,100 ± 2004,700 ± 5002,900 ± 8004,000 ± 8002,900 ± 600>8,8006.67.8 4-chlorophenethylh24 ± 9700 ± 90160 ± 20420 ± 140640 ± 601,800 ± 70650 ± 210210 ± 900d1,800 ± 6002,400 ± 700680 ± 240610 ± 15075.04.3 4-chlorophenpropylh440 ± 1502,900 ± 900290 ± 901,400 ± 400700 ± 2001,500 ± 2001,600 ± 3001,200 ± 400490 ± 1001,500 ± 200600 ± 1401,700 ± 2001.12.1 4-chloro3-pentylh400 ± 80>5,700240 ± 601,200 ± 903,900 ± 3004,800 ± 1,100>9,400>9,600970 ± 2904,300 ± 200330 ± 803,800 ± 302.41.4 4-chlorocyclopentylh36 ± 10690 ± 14027 ± 8.3240 ± 305,700 ± 1,1004,600 ± 7004,600 ± 8004,200 ± 900380 ± 1203,300 ± 80044 ± 181,000 ± 30011.01.6 3-chloroisobutylh3.7 ± 1.1140 ± 302.8 ± 0.488 ± 123,200 ± 4003,200 ± 4002,100 ± 100870 ± 23023 ± 6340 ± 5014 ± 173 ± 56.25.0 3,4-dichlorocooch3h1.4 ± 0.190 ± 1423 ± 3800 ± 1101,600 ± 1502,500 ± 420540 ± 1101,100 ± 9014 ± 64,200 ± 1,90010 ± 1190 ± 5010.00.43 3,4-dichloropropylh0.97 ± 0.3143 ± 94.5 ± 0.488 ± 321,800 ± 500450 ± 80560 ± 120180 ± 603.9 ± 1.430 ± 88.1 ± 3.847 ± 224.01.8 3,4-dichlorobutylh2.3 ± 0.229 ± 55.7 ± 0.567 ±