DA-Phen

Synthetic dopamine prodrug From Wikipedia, the free encyclopedia

DA-Phen, also known as dopamine–phenylalanine conjugate, is a synthetic dopamine prodrug which is under preclinical evaluation.^[1]^[2]^[3]^[4]^[5]^[6]^[7] Dopamine itself is hydrophilic and is unable to cross the blood–brain barrier, thus showing peripheral selectivity.^[2] DA-Phen was developed as a dopamine prodrug that would allow for entry into the central nervous system via passive diffusion and/or active transport.^[1]^[2]

Other namesDA-Phe; DA-PHEN; Dopamine–phenylalanine conjugate

Drug classMonoamine precursor; Dopamine receptor agonist

CAS Number

54653-55-3^Y

PubChem CID

21426279

Quick facts Clinical data, Other names ...

DA-Phen
Clinical data

Other names	DA-Phe; DA-PHEN; Dopamine–phenylalanine conjugate
Drug class	Monoamine precursor; Dopamine receptor agonist
Identifiers
IUPAC name 2-amino-N-[2-(3,4-dihydroxyphenyl)ethyl]-3-phenylpropanamide
CAS Number	54653-55-3^Y
PubChem CID	21426279
ChemSpider	9522051
Chemical and physical data
Formula	C₁₇H₂₀N₂O₃
Molar mass	300.358 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C1=CC=C(C=C1)CC(C(=O)NCCC2=CC(=C(C=C2)O)O)N
InChI InChI=1S/C17H20N2O3/c18-14(10-12-4-2-1-3-5-12)17(22)19-9-8-13-6-7-15(20)16(21)11-13/h1-7,11,14,20-21H,8-10,18H2,(H,19,22) Key:NBYUYHYHFPOSLI-UHFFFAOYSA-N

DA-Phen is a conjugate of dopamine and the amino acid phenylalanine (Phe or Phen).^[1]^[2] It is slowly cleaved by brain enzymes (t_½ = 460 minutes) to yield free dopamine but is also rapidly hydrolyzed in human blood plasma (t_½ = 28 minutes).^[2] The drug was intended as a prodrug but may also directly interact with the dopamine D₁-like and/or D₂-like receptors.^[1]^[5]^[4]^[6] DA-Phen has shown centrally mediated effects in animals, including increased cognitive flexibility, improved spatial learning and memory, antidepressant- and anxiolytic-like effects, and decreased ethanol intake.^[1]^[7]^[5]

Other analogues, such as DA-Trp and DA-Leu, have also been developed and studied.^[4]

References

[1]
Sutera FM, De Caro V, Giannola LI (January 2017). "Small endogenous molecules as moiety to improve targeting of CNS drugs". Expert Opinion on Drug Delivery. 14 (1): 93–107. doi:10.1080/17425247.2016.1208651. PMID 27367188. Recently, DA has been conjugated with Phe (DA-Phen, Fig 2A) and other Phe mono substituted moieties obtaining related neurotransmitter derivatives capable of carrying DA into the CNS [35,36]. In particular, the physicochemical properties of DA-Phen, e.g. molecular weight and LogD, are favourable for its ability in crossing biological membranes [35]. The aptitude of DA-Phen to reach the CNS has been assessed in a combined approach in vitro, using the PAMPA-BBB and Caco-2 models. Transport across the BBB substantially occurred through transcellular permeation, involving carrier-mediated processes. Molecular docking analysis evidenced that this conjugate interacts with the deep pocket of the identified D1 binding site of the human brain receptor [37]. Following administration on rats, DA-Phen showed a consistent enhancement in cognitive flexibility in naïve subjects, whereas in rats who are trained to alcohol self-administration the conjugate is able to reduce both ethanol intake and forced abstinence signs [38].
[2]
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. 1.5. Peptide Transport-Mediated Prodrugs Giannola et al. [80] have proposed a 2-amino-N-[2-(3,4-dihydroxyphenyl)-ethyl]-3-phenyl-propionamide dopamine prodrug (DA-PHEN) (Figure 10) [81]. It was synthesized by condensation of dopamine with a neutral amino acid to interact with the BBB endogenous transporters and readily enter the CNS. DA-PHEN undergoes slow cleavage by cerebral enzymes (t 1/2 460 min) and yields free dopamine in the brain, but it is rapidly hydrolyzed in human plasma (t 1/2 28 min). Chemical stability studies on DA-PHEN proved that no DA release happened in the gastrointestinal tract, also the prodrug can cross through a simulated intestinal mucosal membrane. Recently, De Caro et al. [81] studied in vitro the ability of DA-PHEN to penetrate the CNS. The team used in their study parallel artificial permeability assay (PAMPA) and Caco-2 models. Despite the relatively low molecular weight (300.35 Da) and the estimated experimental value [80] of log DPh 7.4 (0.76) of DA-PHEN which indicates good potential for passage through biological membranes, they noticed very limited transport through PAMPA-BBB [81]. In fact, the apparent permeability was 3.2 × 107 cm/s, indicating low capacity of DA-PHEN to penetrate BBB by passive transcellular route. Transport trials via Caco-2 cells showed marked increase of DA-PHEN flux with regard to that calculated in PAMPA-BBB system. However, high penetration rates seen in DA-PHEN cannot be obtained only by the simple diffusion, but may also involve carrier mediated transport [82].
[3]
Di Battista V, Hey-Hawkins E (May 2022). "Development of Prodrugs for Treatment of Parkinson's Disease: New Inorganic Scaffolds for Blood-Brain Barrier Permeation". Journal of Pharmaceutical Sciences. 111 (5): 1262–1279. doi:10.1016/j.xphs.2022.02.005. PMID 35182542. DA-PHEN (XXXXI): can be classified as a dopamine prodrug, belonging to the group of peptide transport-mediated prodrugs. It can easily cross the BBB and reach the CNS; it has been proposed that the molecule can also act as a per se drug which modulates cognitive performances correlated with dopaminergic neurotransmission. Preclinical studies will be the next step to be performed.
[4]
Tutone M, Chinnici A, Almerico AM, Perricone U, Sutera FM, De Caro V (November 2016). "Design, synthesis and preliminary evaluation of dopamine-amino acid conjugates as potential D1 dopaminergic modulators". European Journal of Medicinal Chemistry. 124: 435–444. doi:10.1016/j.ejmech.2016.08.051. PMID 27597419.
[5]
De Caro V, Sutera FM, Gentile C, Tutone M, Livrea MA, Almerico AM, et al. (December 2015). "Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation". Journal of Drug Targeting. 23 (10): 910–925. doi:10.3109/1061186X.2015.1035275. PMID 26000952.
[6]
Sutera FM, Giannola LI, Murgia D, De Caro V (December 2017). "Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent". Computational Biology and Chemistry. 71: 63–69. doi:10.1016/j.compbiolchem.2017.09.012. PMID 28985485.
[7]
Sutera FM, De Caro V, Cannizzaro C, Giannola LI, Lavanco G, Plescia F (September 2016). "Effects of DA-Phen, a dopamine-aminoacidic conjugate, on alcohol intake and forced abstinence". Behavioural Brain Research. 310: 109–118. doi:10.1016/j.bbr.2016.05.006. PMID 27155501.

DA-Phen

See also

References

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