O,O′-Dipivaloyldopamine

Synthetic dopamine prodrug From Wikipedia, the free encyclopedia

O,O′-Dipivaloyldopamine, or simply dipivaloyldopamine, also known as 3,4-dipivaloyloxyphenethylamine, is a synthetic derivative of dopamine in which both of the hydroxyl groups have been acetylated.^[1]^[2]^[3]^[4] It was developed as a lipophilic prodrug of dopamine that would allow for entry of dopamine into the central nervous system.^[1]^[2]^[3]^[4]

Other namesDipivaloyldopamine; Dipivaloyl dopamine; Dipivalyldopamine; Dipivalyl dopamine; Dopamine dipivalate; 3,4-Dipivaloyloxyphenethylamine; 3,4-Dipivaloyloxy-2-phenylethylamine

CAS Number

48198-89-6

PubChem CID

14280486

ChemSpider

14331814

Quick facts Clinical data, Other names ...

O,O′-Dipivaloyldopamine
Clinical data

Other names	Dipivaloyldopamine; Dipivaloyl dopamine; Dipivalyldopamine; Dipivalyl dopamine; Dopamine dipivalate; 3,4-Dipivaloyloxyphenethylamine; 3,4-Dipivaloyloxy-2-phenylethylamine
Identifiers
IUPAC name [4-(2-aminoethyl)-2-(2,2-dimethylpropanoyloxy)phenyl] 2,2-dimethylpropanoate
CAS Number	48198-89-6
PubChem CID	14280486
ChemSpider	14331814
Chemical and physical data
Formula	C₁₈H₂₇NO₄
Molar mass	321.417 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CC(C)(C)C(=O)OC1=C(C=C(C=C1)CCN)OC(=O)C(C)(C)C
InChI InChI=1S/C18H27NO4/c1-17(2,3)15(20)22-13-8-7-12(9-10-19)11-14(13)23-16(21)18(4,5)6/h7-8,11H,9-10,19H2,1-6H3 Key:YERQWGUWIPSYAS-UHFFFAOYSA-N

Dopamine itself is too hydrophilic to cross the blood–brain barrier and hence is peripherally selective.^[5]^[2] This, in part, prevents dopamine itself from being employed medically for central nervous system uses.^[5]^[2] Whereas the experimental log P of dopamine is -0.98,^[6] the predicted log P (XLogP3) of O,O'-dipivaloyldopamine is 3.1.^[7] The optimal log P for brain permeation and central activity is at least 1.5.^[8]^[9]

O,O′-Dipivaloyldopamine produced hypothermia in animals, thought to be a centrally mediated dopaminergic effect, but failed to reverse behavioral depression induced by the monoamine depleting agent reserpine.^[3] On the other hand, another analogue, N,N-dimethyl-O,O′-dipivaloyldopamine (XLogP3 = 4.1),^[10] produced both hypothermia and reversed reserpine-induced behavioral depression.^[3]

References

[1]
Campos Rosa JM (22 April 2024). "3 Dopamine". Pharmaceutical Chemistry. De Gruyter. pp. 63–82. doi:10.1515/9783111316888-003. ISBN 978-3-11-131688-8. Dopamine is very hydrophilic, which means that it can neither be absorbed well orally, nor does it cross the BBB. In contrast, L-dopa is properly absorbed by active transport mechanisms, and, once in the brain, it is decarboxylated and produces dopamine, thus behaving as a prodrug of dopamine (Fig. 3.4). In practice, to avoid side effects, it is necessary to combine L-dopa with peripheral dopa decarboxylase inhibitors, such as α-(S)-methyl-DOPA, carbidopa, or benserazide (Fig. 3.5). A strategy that allows the passage of dopamine through the BBB, if it has been adequately latentized (Fig. 3.6) in the form of the dipivaloyl dopamine prodrug, has been developed. Fig. 3.6: Administration of the dipivaloyl dopamine prodrug.
[2]
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].
[3]
Walker RB, Ayres JW, Block JH, Lock A (April 1978). "tert-Butoxycarbanyl as a convenient protecting group in synthesis of potential centrally active dopamine derivatives". J Pharm Sci. 67 (4): 558–559. doi:10.1002/jps.2600670433. PMID 641771. Casagrande and Ferrari (3) synthesized 4-pivaloyl- and 3,4-dipivaloyldopamine plus several other dopamine esters containing more bulky acyloxy groups and suggested, without providing pharmacological data, that these compounds would provide sufficient lipophilicity and resistance to hydrolysis for entry into the central nervous system (CNS) before releasing the parent phenethylamine. [...] Esters (II-IV) and amides (V and VI) of dopamine (I) containing either the pivaloyl or pivaloyloxy function were, therefore, synthesized and examined in mice for hypothermic activity and the ability to reverse reserpine-induced motor depression. [...] Biological Activity-Preliminary tests of five analogs of pivaloyl and pivaloyloxy esters and amides of dopamine were examined for potential antiparkinson activity. The two models used to estimate the agent's ability to stimulate dopaminergic receptors were the production of hypothermia (5, 6) and the antagonism of reserpine-induced motor depression in mice (15). [...] All compounds tested elicited hypothermic responses in mice 90 min after intraperitoneal injection. However, it is not possible to conclude from these preliminary results that the hypothermia elicited in mice following the administration of the test compounds was due to central dopaminergic stimulation, except perhaps for III, which also elicited a positive reserpine-induced motor depression reversal response.
[4]
Casagrande C, Ferrari G (February 1973). "3,4-0-diacyl derivatives of dopamine". Farmaco Sci. 28 (2): 143–148. PMID 4692789.
[5]
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.
[6]
"Dopamine". PubChem. Retrieved 30 September 2024.
[7]
"[4-(2-Aminoethyl)-2-(2,2-dimethylpropanoyloxy)phenyl] 2,2-dimethylpropanoate". PubChem. Retrieved 30 September 2024.
[8]
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
[9]
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
[10]
"[4-[2-(Dimethylamino)ethyl]-2-(2,2-dimethylpropanoyloxy)phenyl] 2,2-dimethylpropanoate". PubChem. Retrieved 30 September 2024.

O,O′-Dipivaloyldopamine

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