CTDP-32476

CTDP-32476
Identifiers
  • (2R)-2-[(1R)-1-(4-chlorophenyl)-3-methylbutyl]piperidine
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC16H24ClN
Molar mass265.83 g·mol−1
3D model (JSmol)
  • CC(C)C[C@H]([C@@H]1CCCCN1)C2=CC=C(C=C2)Cl
  • InChI=1S/C16H24ClN/c1-12(2)11-15(16-5-3-4-10-18-16)13-6-8-14(17)9-7-13/h6-9,12,15-16,18H,3-5,10-11H2,1-2H3/t15-,16-/m0/s1
  • Key:UWHKVOABKKOHHU-HOTGVXAUSA-N

CTDP-32476 is an atypical, highly potent dopamine reuptake inhibitor investigated as a potential pharmacotherapy for cocaine addiction.[1][2][3] Unlike cocaine, which acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) by rapidly blocking reuptake of all three monoamines, CTDP-32476 is highly selective for the dopamine transporter (DAT) and does not significantly block either the serotonin or norepinephrine transporters. Its slow-onset and long-duration effects are thought to result from pharmacokinetic properties such as delayed absorption and slower diffusion across the blood-brain barrier (BBB), resulting in a much lower risk of abuse compared to cocaine. However, the evidence for slower BBB penetration is indirect and inferred primarily from behavioral and neurochemical profiles rather than direct permeability measurements. While agonist-replacement therapies have been effective for opiate and nicotine dependence, there is currently no reliably successful agent for cocaine addiction.[4]

The two enantiomers were labeled ATDP-34209 and ATDP-34210. Their absolute configurations were determined by X-ray crystallography. ATDP-34210 is the RR enantiomer corresponding to the active RR enantiomer of methylphenidate. Both the SS and the RR enantiomers have similar activities.[3]

Synthesis

The starting quaternary phosphonium salt is called isobutyltriphenylphosphonium bromide (1a). Treatment with phenyl lithium gives the corresponding ylide p-(i-butylidene)triphenylphosphorane (1b). The Wittig reaction with 2-(4-chlorobenzoyl)pyridine (2) gives a pair of geometric isomers: 2-[(E)-1-(4-chlorophenyl)-3-methylbut-1-enyl]pyridine (3) & 2-[(Z)-1-(4-chlorophenyl)-3-methylbut-1-enyl]pyridine (4). Catalytic hydrogenation completes the synthesis (5).[3]

The geometric isomers can be resolved using the corresponding acetylleucine enantiomers.[3]

See also

References

  1. ^ Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, et al. (January 2007). "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". Journal of Medicinal Chemistry. 50 (2): 219–232. doi:10.1021/jm0608614. PMID 17228864.
  2. ^ Xi ZX, Song R, Li X, Lu GY, Peng XQ, He Y, et al. (February 2017). "CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction". Neuropsychopharmacology. 42 (3): 682–694. doi:10.1038/npp.2016.155. PMC 5240176. PMID 27534265.
  3. ^ a b c d Froimowitz M, Taboada R, Poulos ZJ, Rainone DJ, Imler GH, Gardner EL, et al. (October 2023). "Chiral Resolution of the Enantiomers of the Slow-Onset Dopamine Reuptake Inhibitor CTDP-32476 and Their Activities". ACS Omega. 8 (39): 35738–35745. doi:10.1021/acsomega.3c02997. PMC 10552101. PMID 37810691.
  4. ^ Jordan CJ, Cao J, Newman AH, Xi ZX (November 2019). "Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine". Neuropharmacology. 158 107609. doi:10.1016/j.neuropharm.2019.04.015. PMC 6745247. PMID 31009632.
  5. ^ Gardner EL, Liu X, Paredes W, Giordano A, Spector J, Lepore M, et al. (October 2006). "A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: effects in laboratory rat models relating to addiction". Neuropharmacology. 51 (5): 993–1003. doi:10.1016/j.neuropharm.2006.06.009. PMID 16901516.
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