1.Photocontrollable peroxynitrite generator based on N-methyl-N-nitrosoaminophenol for cellular application
J Am Chem Soc. 2012 Feb 8;134(5):2563-8. doi: 10.1021/ja206744z.
We designed and synthesized a photocontrollable peroxynitrite (ONOO(-)) generator, P-NAP, which has N-methyl-N-nitrosoaminophenol structure with four methyl groups introduced onto the benzene ring to block reaction of the photodecomposition product with ONOO(-) and to lower the semiquinoneimine's redox potential. The semiquinoneimine intermediate generated by photoinduced release of nitric oxide (NO) reduces dissolved molecular oxygen to generate superoxide radical anion (O(2)(•-)), which reacts with NO to afford ONOO(-) under diffusion control (k = 6.7 × 10(9) M(-1) s(-1)). NO release from P-NAP under UV-A (330-380 nm) irradiation was confirmed by ESR spin trapping. Tyrosine nitration, characteristic of ONOO(-), was demonstrated by HPLC analysis of a photoirradiated aqueous solution of P-NAP and N-acetyl-l-tyrosine ethyl ester. ONOO(-) formation was confirmed with a ONOO(-)-specific fluorogenic probe, HKGreen-3, and compared with that from 3-(4-morpholinyl)sydnonimine hydrochloride (SIN-1), which is the most widely used ONOO(-) generator at present. The photoreaction of P-NAP was influenced by superoxide dismutase, indicating that generation of O(2)(•-) occurs before ONOO(-) formation. The quantum yield for formation of duroquinone, the main P-NAP photodecomposition product, was measured as 0.86 ± 0.07 at 334 nm with a potassium ferrioxalate actinometer. Generation of ONOO(-) from P-NAP in HCT-116 cells upon photoirradiation was successfully imaged with HKGreen-3A. This is the first example of a photocontrollable ONOO(-) donor applicable to cultured cells.
2.Plasma concentration of alpha-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester
Eur J Clin Pharmacol. 1975 Aug 14;8(6):381-6. doi: 10.1007/BF00562310.
The plasma concentrations of free alpha-methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following alpha-methyldopa (1 g) orally. Five of these patients subsequently received alpha-methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of alpha-methyldopa intravenously. After oral administration a large amount of total plasma alpha-methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated alpha-methyldopa in plasma (ratio at 4 hours ranged from 3.73-0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous alpha-methyldopa than alpha-methyldopate. The plasma concentration of alpha-methyldopa (free and esterified) 60 minutes after i.v. alpha-methyldopate was 1.7+/-0.3 mug/ml while at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 mug/ml. Although small amounts of sulphate conjugate were detected after i.v. alpha-methyldopate, insignificant quantities of conjugate were found after i.v. alpha-methyldopa. The average fall in mean arterial pressure was 27 mm/Hg following i.v. alpha-methyldopa but only 2.7 mm Hg following alpha-methyldopate. These results suggest that sulphate conjugation of alpha-methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of alpha-methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free alpha-methyldopa have been demonstrated.
3.Novel L-Dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety
Pharm Res. 2007 Jul;24(7):1309-24. doi: 10.1007/s11095-007-9255-y.
Purpose:
The aim of this study was to gain insight into the feasibility of enhancing the delivery of L-Dopa and dopamine to the brain by linking these neurotransmitters and L-Dopa ethyl ester to 2-phenyl-3-carboxymethyl-imidazopyridine compounds giving rise to the so-called Dopimid compounds.
Materials and methods:
A number of Dopimid compounds were synthesized and both stability and binding studies to dopaminergic and benzodiazepine receptors were performed. To evaluate whether Dopimid compounds are P-gp substrates, [(3)H]ritonavir uptake experiments and bi-directional transport studies on confluent MDCKII-MDR1 monolayers were carried out. The brain penetration properties of Dopimid compounds were estimated by the Clark's computational model and evaluated by investigation of their transport across BBMECs monolayers. The dopamine levels following the intraperitoneal administration of the selected Dopimid compounds were measured in vivo by using brain microdialysis in rat.
Results:
Tested compounds were adequately stable in solution buffered at pH 7.4 but undergo faster cleavage in dilute rat serum at 37 degrees C. Receptor binding studies showed that Dopimid compounds are essentially devoid of affinity for dopaminergic and benzodiazepine receptors. [(3)H]ritonavir uptake experiments indicated that selected Dopimid compounds, like L-Dopa and dopamine hydrochloride, are not substrates of P-gp and it was also confirmed by bi-directional transport experiments across MDCKII-MDR1 monolayers. By Clark's model a significant brain penetration was deduced for L-Dopa ethyl ester and dopamine derivatives. Transport studies involving BBMECs monolayers indicated that some of these compounds should be able to cross the BBB. Interestingly, the rank order of apparent permeability (P (app)) values observed in these assays parallels that calculated by the computational approach. Brain microdialysis experiments in rat showed that intraperitoneal acute administration of some Dopimid compounds induced a dose-dependent increase in cortical dopamine output.
Conclusion:
Based on these results, it may be concluded that some Dopimid compounds can be proposed as novel L-Dopa and dopamine prodrugs.
