Substituted phenidates

Overview

Substituted phenidates (also known as phenidates) refer to a class of compounds that predominantly produce traditional stimulant effects when administered. A substituted phenidate may be defined as an ester of ritalinic acid and its analogs. PW

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.[1][2][3] WP

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.[4][5] WP

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).[6] WP⚠ The source has a footnote here that is not shown.

References

1. Journal / agency 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 Testing and Analysis. March 2017. doi:10.1002/dta.2161 · PMID 28067464
2. Journal / agency Luethi D, Kaeser PJ, Brandt SD, Krähenbühl S, Hoener MC, Liechti ME. Pharmacological profile of methylphenidate-based designer drugs. Neuropharmacology. May 2018. doi:10.1016/j.neuropharm.2017.08.020 · PMID 28823611
3. Journal / agency Carlier J, Giorgetti R, Varì MR, Pirani F, Ricci G, Busardò FP. Use of cognitive enhancers: methylphenidate and analogs. European Review for Medical and Pharmacological Sciences. January 2019. doi:10.26355/eurrev_201901_16741 · PMID 30657540
4. Journal / agency Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A. Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. Journal of Medicinal Chemistry. January 2007. doi:10.1021/jm0608614 · PMID 17228864
5. Journal / agency Misra M, Shi Q, Ye X, Gruszecka-Kowalik E, Bu W, Liu Z, Schweri MM, Deutsch HM, Venanzi CA. Quantitative structure-activity relationship studies of threo-methylphenidate analogs. Bioorg Med Chem. 2010. doi:10.1016/j.bmc.2010.08.034 · PMID 20846865
6. Journal / agency Singh, Satendra. Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Chem. Rev. 2000. doi:10.1021/cr9700538 · PMID 11749256

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