CTDP-32476
 | |
| Identifiers | |
|---|---|
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| Chemical and physical data | |
| Formula | C16H24ClN |
| Molar mass | 265.83 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
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.[citation needed] 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
[edit]
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
[edit]- Sibutramine
- Indatraline (30,640 is N-methyl-Indatraline)[5]
- RTI-336
- PR-000608
- List of methylphenidate analogues
References
[edit]- ↑ 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.
- ↑ 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.
- 1 2 3 4 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.
- ↑ 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.
- ↑ 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.