O,O′-Diacetyldopamine, or 3,4-O-diacetyldopamine, also known as 3,4-diacetoxyphenethylamine, is a synthetic derivative of dopamine in which both of the hydroxyl groups have been acetylated.[1][2][3][4]
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| Other names | 3,4-O-Diacetyldopamine; 3,4-Diacetoxyphenethylamine; 3,4-Diacetoxy-2-phenylethylamine |
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| Formula | C12H15NO4 |
| Molar mass | 237.255 g·mol−1 |
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Description
editThe drug was an attempt at creating a more lipophilic analogue and prodrug of dopamine which could potentially be used medically for central nervous system indications like treatment of Parkinson's disease.[1][2][3][4]
Dopamine itself is too hydrophilic to cross the blood–brain barrier and hence is peripherally selective.[1][2] This, in part, prevents dopamine itself from being employed pharmaceutically for such uses.[1][2] Whereas the experimental log P of dopamine is -0.98,[5] the predicted log P (XLogP3) of O,O′-diacetyldopamine is 0.3.[6] The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).[7][8]
O,O′-Diacetyldopamine proved to be inactive in animal behavioral tests.[1][4] This suggests that dopamine O-acetylation alone is insufficient to allow for brain permeability.[1][4] However, synthetic dopamine derivatives that were both O-acetylated and N-alkylated, with further increased lipophilicity, for instance N,N-dimethyl-O,O′-acetyldopamine (XLogP3 = 1.3),[9] were robustly active in behavioral tests, including reversal of behavioral depression induced by the dopamine depleting agent tetrabenazine.[4]
Other dopamine analogues and prodrugs have also been developed and studied.[1][10][11][12]
See also
editReferences
edit- ^ a b c d e f g Haddad F, Sawalha M, Khawaja Y, Najjar A, Karaman R (December 2017). "Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease". Molecules. 23 (1): 40. doi:10.3390/molecules23010040. PMC 5943940. PMID 29295587.
- ^ a b c d Di Stefano A, Sozio P, Cerasa LS (January 2008). "Antiparkinson prodrugs". Molecules. 13 (1): 46–68. doi:10.3390/molecules13010046. PMC 6244951. PMID 18259129.
Dopamine prodrugs [...] DA is subject to extensive hepatic metabolism following oral administration. Due to the presence of the catechol moiety it is essentially completely ionized at physiological pH, which results in its poor permeation across the BBB and other cell membranes. For these reasons the use of DA itself in PD treatment is precluded [22]. To overcome these problems a series of lipophilic 3,4-O-diesters 1-5 (Figure 1) were proposed as latent lipophilic derivatives of DA usable in therapy of parkinsonism, hypertension and renal failure [23, 24].
- ^ a b Casagrande C, Ferrari G (February 1973). "3,4-0-diacyl derivatives of dopamine". Farmaco Sci. 28 (2): 143–148. PMID 4692789.
- ^ a b c d e Borgman RJ, Mcphillips JJ, Stitzel RE, Goodman IJ (June 1973). "Synthesis and pharmacology of centrally acting dopamine derivatives qnd analogs in relation to parkinson's disease". J Med Chem. 16 (6): 630–633. doi:10.1021/jm00264a011. PMID 4714993.
- ^ "Dopamine". PubChem. U.S. National Library of Medicine. Retrieved 30 September 2024.
- ^ "[2-Acetyloxy-4-(2-aminoethyl)phenyl] acetate". PubChem. U.S. National Library of Medicine. Retrieved 30 September 2024.
- ^ Pajouhesh H, Lenz GR (October 2005). "Medicinal chemical properties of successful central nervous system drugs". NeuroRx. 2 (4): 541–553. doi:10.1602/neurorx.2.4.541. PMC 1201314. PMID 16489364.
Lipophilicity was the first of the descriptors to be identified as important for CNS penetration. Hansch and Leo54 reasoned that highly lipophilic molecules will partitioned into the lipid interior of membranes and will be retained there. However, ClogP correlates nicely with LogBBB with increasing lipophilicity increasing brain penetration. For several classes of CNS active substances, Hansch and Leo54 found that blood-brain barrier penetration is optimal when the LogP values are in the range of 1.5-2.7, with the mean value of 2.1. An analysis of small drug-like molecules suggested that for better brain permeation46 and for good intestinal permeability55 the LogD values need to be greater than 0 and less than 3. In comparison, the mean value for ClogP for the marketed CNS drugs is 2.5, which is in good agreement with the range found by Hansch et al.22
- ^ Mikitsh JL, Chacko AM (2014). "Pathways for small molecule delivery to the central nervous system across the blood-brain barrier". Perspect Medicin Chem. 6: 11–24. doi:10.4137/PMC.S13384. PMC 4064947. PMID 24963272.
For small molecules in particular, lipophilicity, as measured by log P, can be an excellent indicator of BBB permeability. To cross the hydrophobic phospholipid bilayer of a cell membrane by passive diffusion, a molecule must be lipophilic. Hydrophilic substances do not possess the ability to penetrate such membranes. Initial thought was that the higher the log P, the higher the BBB permeability.54 However, given that log P values range for most drugs between −0.05 and 6.0,58 the ideal range for BBB permeability has been found to be 1.5–2.5.53
- ^ "[2-Acetyloxy-4-[2-(dimethylamino)ethyl]phenyl] acetate". PubChem. U.S. National Library of Medicine. Retrieved 30 September 2024.
- ^ Stella VJ, Kearney AS (1991). "Pharmacokinetics of Drug Targeting: Specific Implications for Targeting via Prodrugs". Handbook of Experimental Pharmacology. Vol. 100. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 71–103. doi:10.1007/978-3-642-75862-1_4. ISBN 978-3-642-75864-5. ISSN 0171-2004.
[D]opamine, administered intravenously, is unable to permeate the blood-brain barrier (BBB) in therapeutically significant quantities (Roos and STEG 1964); therefore, delivery approaches utilizing lipophilic prodrugs of dopamine have been tried. The monobenzoyl and dibenzoyl ester prodrugs of dopamine were synthesized in an attempt to improve the delivery of the parent drug, via these lipophilic prodrugs, to the brain (TEJANI-BulT et al. 1988). A comparison of the n-octanollphosphate buffer partition coefficients revealed that the monoester was approximately 300-fold more lipophilic and that the diester was about 20,000-fold more lipophilic than the parent compound. In addition, the monoester was found to be 28-fold more rapidly hydrolyzed than the diester at physiological pH. Following the intravenous administration of 8-14C-radiolabelled esters in rats, the mono benzoyl ester was apparently unable to penetrate into the brain due to insufficient lipophilicity and/or premature bioreversion, whereas the dibenzoyl ester readily penetrated into the brain. Even though the dibenzoyl prodrug was able to reach to target site, it did not result in significant increases in the brain levels of dopamine or dihydroxyphenylacetic acid, one of its major metablites. This finding may be attributed to the prodrug having a clearance rate from the site that is more rapid than its conversion rate to the drug at the site.
- ^ Tejani-Butt SM, Hauptmann M, D'Mello A, Frazer A, Marcoccia JM, Brunswick DJ (November 1988). "Evaluation of mono- and dibenzoyl esters of dopamine as potential pro-drugs for dopamine in the central nervous system". Naunyn Schmiedebergs Arch Pharmacol. 338 (5): 497–503. doi:10.1007/BF00179320. PMID 3244391.
- ^ Casagrande C, Santangelo F (1989). "Dopaminergic Prodrugs". Peripheral Dopamine Pathophysiology. CRC Press. pp. 307–346. doi:10.1201/9780429278297-26. ISBN 978-0-429-27829-7.
11. CNS-TARGETED DOPAMINERGIC PRODRUGS Levodopa (Figure 1) still remains the only precursor of DA clinically employed in the treatment of Parkinson disease; of several attempts made to obtain new drugs by improving the CNS delivery of DA or structurally related compounds, some have shown interesting pharmacological results, but none has shown properties to warrant clinical investigations. Examples of esters of N-substituted dopamines, such as 3,4-O-diacetyl-N,N- dimethyldopamine or 3,4-O-dipivaloyl-N,N-di-n-propyl-dopamine (Figure 3) have been discussed by Wikstrom et al.14 and Borgman et al.15 N-(N-methyldihydronicotinoyl) derivatives of DA (Fi re 2) have been considered in the preceding section.