DA-Phen

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, also known as dopamine–phenylalanine conjugate, is a synthetic dopamine prodrug which is under preclinical evaluation.¹²³⁴⁵⁶⁷ 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.¹²

DA-Phen is a conjugate of dopamine and the amino acid phenylalanine (Phe or Phen).¹² 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.¹⁵⁴⁶ 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.¹⁷⁵

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

References

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].
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].
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.
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.
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.
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.
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.

[SuteraDeCaroGianolla2017-1] 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].

[HaddadSawalhaKhawaja2017-2] 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].

[DiBattistaHey-Hawkins2022-3] 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.

[TutoneChinniciAlmerico2016-4] 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.

[DeCaroSuteraGentile2015-5] 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.

[SuteraGianncolaMurgia2017-6] 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.

[SuteraDeCaroCannizzaro2016-7] 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.

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References