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2-Benzylpiperidine

2-Benzylpiperidine
Clinical data
Routes of
administration		Oral
Drug classDopamine reuptake inhibitor
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
  • 2-benzylpiperidine
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.046.581 Edit this at Wikidata
Chemical and physical data
FormulaC12H17N
Molar mass175.275 g·mol−1
3D model (JSmol)
  • C1CCNC(C1)CC2=CC=CC=C2
  • InChI=1S/C12H17N/c1-2-6-11(7-3-1)10-12-8-4-5-9-13-12/h1-3,6-7,12-13H,4-5,8-10H2 checkY
  • Key:ITXCORRITGNIHP-UHFFFAOYSA-N checkY
  (verify)

2-Benzylpiperidine is a stimulant drug of the arylpiperidine family. It is similar in structure to certain other stimulants such as methylphenidate and desoxypipradrol. However, it is far less potent as a monoamine reuptake inhibitor in comparison.[1][2][3] The drug is little used as a stimulant, with its main use being as a synthetic intermediate in the manufacture of other drugs.[4][5][6]

Pharmacology

The affinity (Ki) of 2-benzylpiperidine for the dopamine transporter (DAT) has been reported to be 6,360 nM and its functional inhibition (IC50) of the DAT has been reported to be 3,780 to 8,800 nM.[1][2][3] These values were 85-fold and 53- to 38-fold lower than those of methylphenidate, respectively.[1][2][3] It produced 36% inhibition of binding to the norepinephrine transporter (NET) and 22% inhibition of binding to the serotonin transporter (SERT) at a concentration of 10,000 nM.[3] However, 2-phenylpiperidine might have actually been assayed by mistake in one of the two studies that reported the preceding values, and so some of the values might be incorrect.[1] In another older study, 2-benzylpiperidine was reported to be similarly potent to dextroamphetamine in terms of norepinephrine reuptake inhibition.[7]

Anaglogs

Derivatives of 2-benzylpiperidine, such as the cathinone-like derivative α-keto-2-benzylpiperidine and its 4-methyl, 4-halo, and 3,4-dichloro analogues, have been synthesized and have been found to be much more potent as dopamine reuptake inhibitors.[1] Another analogue of 2-benzylpiperidine, 3-phenylpiperidine, is also more potent as a monoamine reuptake inhibitor in comparison, with higher affinities for the monoamine transporters and ~8-fold higher functional inhibition of the DAT.[3]

See also

References

  1. ^ a b c d e Yadav-Samudrala BJ, Eltit JM, Glennon RA (September 2019). "Synthetic Cathinone Analogues Structurally Related to the Central Stimulant Methylphenidate as Dopamine Reuptake Inhibitors". ACS Chem Neurosci. 10 (9): 4043–4050. doi:10.1021/acschemneuro.9b00284. PMID 31369229. Compound 5 [(2-benzylpiperidine)] has also, apparently, been previously prepared and examined as a DAT reuptake inhibitor by Kim et al.6 However, there is a potential problem. Although Kim et al.6 showed the correct chemical structure for 2-benzylpiperidine, their experimental writeup suggests they might have inadvertently prepared 2-phenylpiperidine. Furthermore, their melting point for the target is different from that previously reported by others for the target compound.23,24 Obviously, apart from the different melting point, this might have been a typographical error.
  2. ^ a b c Yadav BJ (16 July 2019). "Understanding Structure-Activity Relationship Of Synthetic Cathinones (Bath Salts) Utilizing Methylphenidate". VCU Scholars Compass. Retrieved 9 December 2024. 8 Complete removal of the ester of tMP (i.e., 2-benzylpiperidine, 130) reduced the binding affinity at DAT by 85-fold (IC50 = 6360 nM) and reduced [ 3H]DA reuptake potency by 38-fold (IC50 = 8800 nM) as compared to tMP (70) (IC50 =75 and 230 nM, binding affinity and [ 3H]DA uptake, respectively).125 [...] We also showed that the carbonyl oxygen atom of 161 is not important for the compound to act as a DAT reuptake inhibitor as our descarbonyl analog (2-benzylpiperidine, 169) retained activity; however, the carbonyl oxygen atom helps to improve the potency at DAT as a reuptake inhibitor.
  3. ^ a b c d e Kim DI, Deutsch HM, Ye X, Schweri MM (May 2007). "Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate". Journal of Medicinal Chemistry. 50 (11): 2718–2731. doi:10.1021/jm061354p. PMID 17489581.
  4. ^ Ablordeppey SY, Fischer JB, Law H, Glennon RA (August 2002). "Probing the proposed phenyl-A region of the sigma-1 receptor". Bioorganic & Medicinal Chemistry. 10 (8): 2759–2765. doi:10.1016/S0968-0896(02)00096-2. PMID 12057665.
  5. ^ Ágai B, Proszenyák A, Tárkányi G, Vida L, Faigl F (2004). "Convenient, Benign and Scalable Synthesis of 2- and 4-Substituted Benzylpiperidines". European Journal of Organic Chemistry. 2004 (17): 3623–3632. doi:10.1002/ejoc.200400215.
  6. ^ US 6124317, Bigge CF, Keana JR, Cai SX, Weber E, Woodward R, Lan NC, Guzikowski AP, "2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists." 
  7. ^ Ferris RM, Tang FL (September 1979). "Comparison of the effects of the isomers of amphetamine, methylphenidate and deoxypipradrol on the uptake of l-[3H]norepinephrine and [3H]dopamine by synaptic vesicles from rat whole brain, striatum and hypothalamus". The Journal of Pharmacology and Experimental Therapeutics. 210 (3): 422–428. PMID 39160. [...] removal of the additional phenyl ring of deoxypipradrol or the carbomethoxy group of methylphenidate yields 2-benzylpiperidine which contains the intact piperidine ring and is as potent as S-(+)-amphetamine as an inhibitor of norepinephrine uptake into synaptic vesicles (unpublished observations). [...]
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