Synthesis and dopamine receptor binding of dihydrexidine and SKF 38393 catecholamine-based analogues.

Dopamine is an important neurotransmitter that regulates numerous essential functions, including cognition and voluntary movement. As such, it serves as an important scaffold for synthesis of novel analogues as part of drug development effort to obtain drugs for treatment of neurodegenerative diseases, such as Parkinson's disease. To that end, similarity search of the ZINC database based on two known dopamine-1 receptor (D1R) agonists, dihydrexidine (DHX) and SKF 38393, respectively, was used to predict novel chemical entities with potential binding to D1R. Three compounds that showed the highest similarity index were selected for synthesis and bioactivity profiling. All main synthesis products as well as the isolated intermediates, were properly characterized. The physico-chemical analyses were performed using HRESIMS, GC/MS, LC/MS with UV-Vis detection, and FTIR, 1H NMR and 13C NMR spectroscopy. Binding to D1 and D2 receptors and inhibition of dopamine reuptake via dopamine transporter were measured for the synthesized analogues of DHX and SKF 38393.

Electrospray ionization tandem mass spectrometry of deprotonated dihydrobenzofuran neolignans.

RATIONALE: Although dihydrobenzofuran neolignans (DBNs) display a wide diversity of biological activities, the identification of their in vivo metabolites using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) remains a challenge to be overcome. Recently, ESI-MS/MS data of protonated DBNs have been reported, but they were shown to be limited due to the scarcity of diagnostic ions. METHODS: The gas-phase fragmentation pathways of a series of biologically active synthetic benzofuran neolignans (BNs) and DBNs were elucidated by means of negative ESI accurate-mass tandem and sequential mass spectrometry, and thermochemical data estimated using computational chemistry and the B3LYP/6-31+G(d,p) model. RESULTS: Deprotonated DBNs produced more diagnostic product ions than the corresponding protonated molecules. Moreover, a series of odd-electron product ions (radical anions) were detected, which has not been reported for protonated DBNs. Direct C2 H3 O2 • elimination from the precursor ion (deprotonated molecule) only occurred for the BNs and can help to distinguish these compounds from the DBNs. The mechanism through which the [M - H - CH3 OH]- ion is formed is strongly dependent on specific structural features. CONCLUSIONS: The negative ion mode provides much more information than the positive ion mode (at least one diagnostic product ion was detected for all the analyzed compounds) and does not require the use of additives to produce the precursor ions (deprotonated molecules).

Detailed 1 H and 13 C NMR structural assignments of four sesquiterpene lactones isolated from Eremanthus elaeagnus (Asteraceae).

A complete 1 H and 13 C NMR analysis for a group of four sesquiterpene lactones isolated from Eremanthus elaeagnus (Asteraceae) is described in this work. 1 H NMR, 13 C {1 H} NMR, gCOSY, gHMQC, and gHMBC experiments were performed to provide sufficient structural information to allow an unequivocal assignment. All hydrogen coupling constants were measured, clarifying all hydrogen signal multiplicities.

An Explanation about the Use of (S)-Citronellal as a Chiral Derivatizing Agent (CDA) in 1H and 13C NMR for Sec-Butylamine, Methylbenzylamine, and Amphetamine: A Theoretical-Experimental Study.

A chiral derivatizing agent (CDA) with the aldehyde function has been widely used in discriminating chiral amines because of the easy formation of imines under mild conditions. There is a preference for the use of cyclic aldehydes as a CDA since their lower conformational flexibility favors the differentiation of the diastereoisomeric derivatives. In this study, the imines obtained from the reaction between (S)-citronellal and the chiral amines (sec-butylamine, methylbenzylamine, and amphetamine) were analyzed by the nuclear Overhauser effect (NOE). Through NOE, it was possible to observe that the ends of the molecules were close, suggesting a quasi-folded conformation. This conformation was confirmed by theoretical calculations that indicated the London forces and the molecular orbitals as main justifications for this conformation. This conformational locking explains the good separation of 13C NMR signals between the diastereomeric imines obtained and, consequently, a good determination of the enantiomeric excess using the open chain (S)-citronellal as a CDA.

Gas-phase fragmentation reactions of protonated benzofuran- and dihydrobenzofuran-type neolignans investigated by accurate-mass electrospray ionization tandem mass spectrometry.

We have investigated gas-phase fragmentation reactions of protonated benzofuran neolignans (BNs) and dihydrobenzofuran neolignans (DBNs) by accurate-mass electrospray ionization tandem and multiple-stage (MSn ) mass spectrometry combined with thermochemical data estimated by Computational Chemistry. Most of the protonated compounds fragment into product ions B ([M + H-MeOH]+ ), C ([B-MeOH]+ ), D ([C-CO]+ ), and E ([D-CO]+ ) upon collision-induced dissociation (CID). However, we identified a series of diagnostic ions and associated them with specific structural features. In the case of compounds displaying an acetoxy group at C-4, product ion C produces diagnostic ions K ([C-C2 H2 O]+ ), L ([K-CO]+ ), and P ([L-CO]+ ). Formation of product ions H ([D-H2 O]+ ) and M ([H-CO]+ ) is associated with the hydroxyl group at C-3 and C-3', whereas product ions N ([D-MeOH]+ ) and O ([N-MeOH]+ ) indicate a methoxyl group at the same positions. Finally, product ions F ([A-C2 H2 O]+ ), Q ([A-C3 H6 O2 ]+ ), I ([A-C6 H6 O]+ ), and J ([I-MeOH]+ ) for DBNs and product ion G ([B-C2 H2 O]+ ) for BNs diagnose a saturated bond between C-7' and C-8'. We used these structure-fragmentation relationships in combination with deuterium exchange experiments, MSn data, and Computational Chemistry to elucidate the gas-phase fragmentation pathways of these compounds. These results could help to elucidate DBN and BN metabolites in in vivo and in vitro studies on the basis of electrospray ionization ESI-CID-MS/MS data only.