DA-Phen

DA-Phen
臨床資料
其他名稱	DA-Phe; DA-PHEN; Dopamine–phenylalanine conjugate
藥物類別	Monoamine precursor; Dopamine receptor agonist
识别信息
	IUPAC命名法 2-amino-N-[2-(3,4-dihydroxyphenyl)ethyl]-3-phenylpropanamide; ;
CAS号	54653-55-3
PubChem CID	21426279;
ChemSpider	9522051;
化学信息
化学式	C17H20N2O3
摩尔质量	300.36 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	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是一种含氮有机化合物，化学式C₁₇H₂₀N₂O₃，为人工合成的多巴胺前体药物^[1]^[2]。

参考资料

^ Sutera FM, De Caro V, Giannola LI. Small endogenous molecules as moiety to improve targeting of CNS drugs. Expert Opinion on Drug Delivery. January 2017, 14 (1): 93–107. PMID 27367188. doi:10.1080/17425247.2016.1208651. 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. Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease. Molecules. December 2017, 23 (1): 40. PMC 5943940 . PMID 29295587. doi:10.3390/molecules23010040 . 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].

[SuteraDeCaroGianolla2017-1] Sutera FM, De Caro V, Giannola LI. Small endogenous molecules as moiety to improve targeting of CNS drugs. Expert Opinion on Drug Delivery. January 2017, 14 (1): 93–107. PMID 27367188. doi:10.1080/17425247.2016.1208651. 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. Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease. Molecules. December 2017, 23 (1): 40. PMC 5943940 . PMID 29295587. doi:10.3390/molecules23010040 . 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].

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