Phenidate General Structure
   HOME

TheInfoList



OR:

This is a list of
methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
(MPH or MPD)
analogues ''Analogues'' (Spanish: ''Análogos'') is a 2023 Chilean science fiction drama film written, scored and directed by Jorge Olguín. Starring Mónica Carrasco and Jorge Gajardo accompanied by Cindy Díaz. It is about an elderly couple who feel alone ...
, 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 Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...
(ADHD) and certain other indications. Several other derivatives including
rimiterol Rimiterol (INN/USAN) is a third-generation short-acting β2 agonist. See also *Isoprenaline Isoprenaline, also known as isoproterenol and sold under the brand name Isuprel among others, is a sympathomimetic medication which is used in th ...
, phacetoperane and
pipradrol Pipradrol, also known by its brand name Meratran, is a mild central nervous system stimulant that acts as a norepinephrine-dopamine reuptake inhibitor. Developed in the United States in the 1940s and patented in 1953, pipradrol was initially m ...
also have more limited medical application. A rather larger number of these compounds have been sold in recent years as
designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...
s, either as quasi-legal substitutes for illicit stimulants such as
methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...
or
cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
, or as purported "study drugs" or
nootropic Nootropics ( or ) (colloquially brain supplements, smart drugs, cognitive enhancers, memory enhancers, or brain boosters) are chemical substances which purportedly improve cognitive functions, such as attention, memory, wakefulness, and self ...
s. More structurally diverse compounds such as
desoxypipradrol Desoxypipradrol, also known as 2-⁠diphenylmethylpiperidine (2-DPMP), is a drug developed by Ciba in the 1950s which acts as a norepinephrine-dopamine reuptake inhibitor (NDRI). Chemistry Desoxypipradrol is closely related on a structural lev ...
(and thus
pipradrol Pipradrol, also known by its brand name Meratran, is a mild central nervous system stimulant that acts as a norepinephrine-dopamine reuptake inhibitor. Developed in the United States in the 1940s and patented in 1953, pipradrol was initially m ...
, including such derivatives as AL-1095, diphemethoxidine, SCH-5472 and D2PM), and even
mefloquine Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It ...
, 2-benzylpiperidine,
rimiterol Rimiterol (INN/USAN) is a third-generation short-acting β2 agonist. See also *Isoprenaline Isoprenaline, also known as isoproterenol and sold under the brand name Isuprel among others, is a sympathomimetic medication which is used in th ...
, enpiroline and
DMBMPP DMBMPP, also known as juncosamine or as 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine, is a highly selective serotonin 5-HT2A receptor agonist and 2-benzylpiperidine analogue of the serotonergic psychedelic 25B-NBOMe which is ...
, can also be considered structurally related, with the former ones also functionally so, as loosely analogous compounds. The
acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an organyl group () or hydrogen in the case of formyl grou ...
group has sometimes been replaced with similar length
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
s to increase duration. Alternatively, the methoxycarbonyl has in some cases been replaced with an
alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...
group. Dozens more phenidates and related compounds are known from the academic and patent literature, and
molecular modelling Molecular modelling encompasses all methods, theoretical and computational, used to model or mimic the behaviour of molecules. The methods are used in the fields of computational chemistry, drug design, computational biology and materials scien ...
and
receptor binding In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recepto ...
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 Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decade ...
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 ( Δ ''s''°, measured using sup>3HBR 1278 @ 25 °C).


Notable phenidate derivatives

;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 Difemetorex (INN) or diphemethoxidine (USAN) is a central nervous system (CNS) stimulant drug introduced in France in 1966 by the pharmaceutical company, Ciba-Geigy; it was briefly used as an appetite suppressant and weight loss aid into the earl ...
, N-benzylethylphenidate), or the
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...
ring replaced by other heterocycles such as
pyrrolidine Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a saturated heterocycle. It is a colourless liquid that is miscible with water and most ...
(e.g.
diphenylprolinol Diphenylprolinol (D2PM), or (''R''/''S'')-(±)-diphenyl-2-pyrrolidinyl-methanol, is a norepinephrine-dopamine reuptake inhibitor which is used as a designer drug. Pharmacology The dextrorotary (''R'')-(+)-enantiomer is the more pharmacologica ...
, 2-Diphenylmethylpyrrolidine),
morpholine Morpholine is an Organic compound, organic chemical compound having the chemical formula oxygen, O(carbon, Chydrogen, H2CH2)2nitrogen, NH. This heterocycle features both amine and ether functional groups. Because of the amine, morpholine is a bas ...
(e.g. Methylmorphenate,
3-Benzhydrylmorpholine 3-Benzhydrylmorpholine is a drug that was developed by American Home Products in the 1950s. It has stimulant and anorectic effects and is related to both pipradrol and phenmetrazine. Synthesis The Ethyl ester of β-Phenylphenylalanine ( Dipheny ...
) or
quinoline Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only sl ...
(e.g. AL-1095, Butyltolylquinuclidine).


Isomerism

Methylphenidate (and its derivatives) have two
chiral center In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...
s, meaning that it, and each of its analogues, have four possible
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
s, each with differing
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
and receptor binding profiles. In practice methylphenidate is most commonly used as pairs of
diastereomer In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have di ...
s 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 Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken by mouth ...
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 Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
. (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 p''K''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 Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...
form is acidic; a
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
(and precursor) known as
ritalinic acid Ritalinic acid is a substituted phenethylamine and an inactive major metabolite of the psychostimulant drugs methylphenidate, dexmethylphenidate and ethylphenidate. When administered orally, methylphenidate is extensively metabolized in the liv ...
. This gives the potential to yield a conjugate
salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...
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 In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used ...
substitutions

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


Piperidine nitrogen methylated phenyl-substituted variants


Cycloalkane In organic chemistry, the cycloalkanes (also called naphthenes, but distinct from naphthalene) are the ring (chemistry), monocyclic Saturated and unsaturated compounds, saturated hydrocarbons. In other words, a cycloalkane consists only of hydroge ...
extensions, contractions & modified derivatives


Azido-iodo-''N''-benzyl analogues

Structures of Azido-iodo-''N''-benzyl analogues of methylphenidate with affinities. *ɑ ''p'' <0.05 versus ''Ki'' of (±)—''threo''-methylphenidate. *b ''p'' <0.05 versus IC50 of (±)—''threo''-methylphenidate. *c ''p'' <0.05 versus its corresponding ''Ki''.


Alkyl substituted-carbomethoxy analogues

*ɑ H = Equivalent overlay of structure sharing functional group *b CO2CH3 (''i.e.'' COOCH3) = Equivalent overlay of structure sharing functional group *c CH3 = Equivalent overlay of structure sharing functional group *d possible 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 Phenmetrazine, sold under the brand name Preludin among others, is a stimulant drug first chemical synthesis, synthesized in 1952 and originally used as an appetite suppressant, but withdrawn drug, withdrawn from the market in the 1980s due to ...
) is 8.3-fold more potent @ DA uptake. *ɑ Compounds tested as hydroclhoride (HCl) salts, unless otherwise noted. *b % inhibition caused by 5''μ''M *c % inhibition caused by 10''μ''M, as assayed by SRI *d Tested as free base *e Assayed by SRI (appropriate correction factor applied.) *f % inhibition of 10''μ''M compound. *g Values expressed as ''x'' ± SEM of 2—5 replicate tests. (If no SEM shown, value is for an ''n'' of 1.) *h Not determined *i ''cf.'' phenmetrazine & derivatives


Various MPH congener affinity values inclusive of norepinephrine & serotonin

Values for ''dl''-''threo''-methylphenidate derivatives are the
mean A mean is a quantity representing the "center" of a collection of numbers and is intermediate to the extreme values of the set of numbers. There are several kinds of means (or "measures of central tendency") in mathematics, especially in statist ...
( 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. *ɑ Denotes 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.


See also

* List of modafinil analogues *
List of cocaine analogues This is a list of cocaine analogues. A cocaine analogue is an (usually) artificial construct of a novel chemical compound from (often the starting point of natural) cocaine's molecular structure, with the result product sufficiently similar to co ...
*
Substituted cathinone Substituted cathinones, or simply cathinones, which include some stimulants and Empathogen-entactogen, entactogens, are chemical derivative, derivatives of cathinone. They feature a substituted phenethylamine, phenethylamine core with an alkyl ...


References


Notes


Further reading

* * * * * * * * * {{Chemical classes of psychoactive drugs Dopamine reuptake inhibitors Norepinephrine–dopamine reuptake inhibitors Carboxylate esters Methyl esters Methylphenidate Piperidines Sigma agonists Sympathomimetic amines Designer drugs Chemical classes of psychoactive drugs