{{Short description|Synthetic dopamine prodrug}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | drug_name = | image = DA-Phen.svg | image_class = skin-invert-image | width = | caption =
<!-- Clinical data --> | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA = | licence_EU = | DailyMedID = | licence_US = | pregnancy_AU = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = | class = Monoamine precursor; Dopamine receptor agonist | ATC_prefix = | ATC_suffix =
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<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 54653-55-3 | CAS_supplemental = | PubChem = 21426279 | IUPHAR_ligand = | DrugBank = | ChemSpiderID = 9522051 | UNII = | KEGG = | ChEBI = | ChEMBL = | NIAID_ChemDB = | PDB_ligand = | synonyms = DA-Phe; DA-PHEN; Dopamine–phenylalanine conjugate
<!-- Chemical data --> | IUPAC_name = 2-amino-''N''-[2-(3,4-dihydroxyphenyl)ethyl]-3-phenylpropanamide | C=17 | H=20 | N=2 | O=3 | SMILES = C1=CC=C(C=C1)CC(C(=O)NCCC2=CC(=C(C=C2)O)O)N | StdInChI = 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) | StdInChIKey = NBYUYHYHFPOSLI-UHFFFAOYSA-N }}
'''DA-Phen''', also known as '''dopamine–phenylalanine conjugate''', is a synthetic dopamine prodrug which is under preclinical evaluation.<ref name="SuteraDeCaroGianolla2017">{{cite journal | vauthors = Sutera FM, De Caro V, Giannola LI | title = Small endogenous molecules as moiety to improve targeting of CNS drugs | journal = Expert Opinion on Drug Delivery | volume = 14 | issue = 1 | pages = 93–107 | date = January 2017 | pmid = 27367188 | doi = 10.1080/17425247.2016.1208651 | quote = 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]. }}</ref><ref name="HaddadSawalhaKhawaja2017">{{cite journal | vauthors = Haddad F, Sawalha M, Khawaja Y, Najjar A, Karaman R | title = Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease | journal = Molecules | volume = 23 | issue = 1 | page = 40 | date = December 2017 | pmid = 29295587 | pmc = 5943940 | doi = 10.3390/molecules23010040 | quote = 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]. | doi-access = free }}</ref><ref name="DiBattistaHey-Hawkins2022">{{cite journal | vauthors = Di Battista V, Hey-Hawkins E | title = Development of Prodrugs for Treatment of Parkinson's Disease: New Inorganic Scaffolds for Blood-Brain Barrier Permeation | journal = Journal of Pharmaceutical Sciences | volume = 111 | issue = 5 | pages = 1262–1279 | date = May 2022 | pmid = 35182542 | doi = 10.1016/j.xphs.2022.02.005 | quote = 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. }}</ref><ref name="TutoneChinniciAlmerico2016">{{cite journal | vauthors = Tutone M, Chinnici A, Almerico AM, Perricone U, Sutera FM, De Caro V | title = Design, synthesis and preliminary evaluation of dopamine-amino acid conjugates as potential D1 dopaminergic modulators | journal = European Journal of Medicinal Chemistry | volume = 124 | issue = | pages = 435–444 | date = November 2016 | pmid = 27597419 | doi = 10.1016/j.ejmech.2016.08.051 }}</ref><ref name="DeCaroSuteraGentile2015">{{cite journal | vauthors = De Caro V, Sutera FM, Gentile C, Tutone M, Livrea MA, Almerico AM, Cannizzaro C, Giannola LI | title = Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation | journal = Journal of Drug Targeting | volume = 23 | issue = 10 | pages = 910–925 | date = December 2015 | pmid = 26000952 | doi = 10.3109/1061186X.2015.1035275 }}</ref><ref name="SuteraGianncolaMurgia2017">{{cite journal | vauthors = Sutera FM, Giannola LI, Murgia D, De Caro V | title = Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent | journal = Computational Biology and Chemistry | volume = 71 | issue = | pages = 63–69 | date = December 2017 | pmid = 28985485 | doi = 10.1016/j.compbiolchem.2017.09.012 }}</ref><ref name="SuteraDeCaroCannizzaro2016">{{cite journal | vauthors = Sutera FM, De Caro V, Cannizzaro C, Giannola LI, Lavanco G, Plescia F | title = Effects of DA-Phen, a dopamine-aminoacidic conjugate, on alcohol intake and forced abstinence | journal = Behavioural Brain Research | volume = 310 | issue = | pages = 109–118 | date = September 2016 | pmid = 27155501 | doi = 10.1016/j.bbr.2016.05.006 }}</ref> Dopamine itself is hydrophilic and is unable to cross the blood–brain barrier, thus showing peripheral selectivity.<ref name="HaddadSawalhaKhawaja2017" /> 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.<ref name="SuteraDeCaroGianolla2017" /><ref name="HaddadSawalhaKhawaja2017" />
DA-Phen is a conjugate of dopamine and the amino acid phenylalanine (Phe or Phen).<ref name="SuteraDeCaroGianolla2017" /><ref name="HaddadSawalhaKhawaja2017" /> It is slowly cleaved by brain enzymes (t<sub>½</sub> = 460{{nbsp}}minutes) to yield free dopamine but is also rapidly hydrolyzed in human blood plasma (t<sub>½</sub> = 28{{nbsp}}minutes).<ref name="HaddadSawalhaKhawaja2017" /> The drug was intended as a prodrug but may also directly interact with the dopamine D<sub>1</sub>-like and/or D<sub>2</sub>-like receptors.<ref name="SuteraDeCaroGianolla2017" /><ref name="DeCaroSuteraGentile2015" /><ref name="TutoneChinniciAlmerico2016" /><ref name="SuteraGianncolaMurgia2017" /> 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.<ref name="SuteraDeCaroGianolla2017" /><ref name="SuteraDeCaroCannizzaro2016" /><ref name="DeCaroSuteraGentile2015" />
Other analogues, such as DA-Trp and DA-Leu, have also been developed and studied.<ref name="TutoneChinniciAlmerico2016" />
== See also == * Neurotransmitter prodrug * Lisdexamfetamine (dextroamphetamine–lysine conjugate) * DopAmide * Docarpamine
== References == {{Reflist}}
{{Dopamine receptor modulators}} {{Phenethylamines}}
Category:Amino acids Category:Catecholamines Category:Dopamine agonists Category:Experimental drugs Category:Monoamine precursors Category:Prodrugs