2-Benzylpiperidine

2-Benzylpiperidine

Clinical data
Routes of administration	Oral
Drug class	Dopamine reuptake inhibitor
ATC code	none
Legal status
Legal status	In general: uncontrolled
Identifiers
IUPAC name 2-benzylpiperidine
CAS Number	32838-55-4  Y
PubChem CID	118004
ChemSpider	105447  Y
UNII	8M5DNQ89DJ
CompTox Dashboard (EPA)	DTXSID40871372
ECHA InfoCard	100.046.581
Chemical and physical data
Formula	C12H17N
Molar mass	175.275 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1CCNC(C1)CC2=CC=CC=C2
InChI 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 Y Key:ITXCORRITGNIHP-UHFFFAOYSA-N Y
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2-Benzylpiperidine is a stimulant drug of the aryl piperidine 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 (K_i) 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]

Analogs

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

• 4-Benzylpiperidine
• 1-Benzylpiperazine

References

1. 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. 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. 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). [...]