José A. Fontenla

Synthesis and biological studies of glycosyl dopamine derivatives as potential antiparkinsonian agents

A new approach to deliver dopamine into the central nervous system, based on the use of D-glucose as transportable agent, has been studied. Glycosyl dopamine derivatives bearing the sugar moiety linked to either the amino group or the catechol ring of dopamine through amide, ester or glycosidic bonds were synthesised as potential antiparkinsonian agents. Studies on the binding to dopamine D2 receptor, in vitro stability, and locomotive effect in mice of the synthetic glycoconjugates are reported.

Synthesis of glycosyl derivatives as dopamine prodrugs: interaction with glucose carrier GLUT-1Electronic supplementary information (ESI) available: experimental details for the preparation of all derivatives and biological assays. See http://www.rsc.org/suppdata/ob/b2/b212066f/

Glucosyl dopamine (DA) derivatives may represent a new class of DA prodrugs that would interact with glucose transporter GLUT-1, present in the blood-brain barrier, and generate DA in the brain. Therefore, compounds bearing the sugar moiety linked to either the amino group or the catechol ring of DA through amide, ester, carbamate, peptide or glycosidic bonds were synthesized. The behavior of the compounds as prodrugs was monitored in different media and the affinity of the glycoconjugates for the glucose carrier GLUT-1 using human erythrocytes was also studied. Most of the compounds were markedly stable in buffer and plasma, and several compounds released DA when incubated with brain extracts and the rate was related to the bond linking DA with glucose. The new glucosyl conjugates substituted at the C-6 position of the sugar were more potent inhibitors of glucose transport when compared to C-1 and C-3 substituted derivatives. This work provides structure-activity information about the interaction of substituted glucose with the GLUT-1 transporter.

Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C receptors#

We describe practical and efficient routes for synthesis of 2-aminomethyl-1,2,3,9-tetrahydro-4H-carbazol-4-ones using the Fischer indole synthesis or palladium-catalysed cyclization methodologies, as well as their affinities for D(2), 5-HT(2A) and 5-HT(2C) receptors, and their activity at the 5-HT(2B) receptor. The most active compounds, 4b (QF 2003B) and 4c (QF 2004B), with a pK(i) (5-HT(2A)/D(2)) ratio of 1.28 show a potential antipsychotic profile according to Meltzers classification.

In vivo effects of new inhibitors of catechol-O-methyl transferase

The effects of two new synthetic compounds showing in vitro catechol‐O‐methyl transferase (COMT) inhibitor properties were studied in vivo and compared with the effects of nitecapone and Ro‐41‐0960. QO IA (3‐(3‐hydroxy‐4‐methoxy‐5‐nitrobenzylidene)‐2,4‐pentanedione), QO IIR ([2‐(3,4‐dihydroxy‐2‐nitrophenyl)vinyl]phenyl ketone), nitecapone and Ro‐41‐0960 (30 mg kg−1, i.p.) were given to reserpinized rats 1 h before the administration of L‐DOPA/carbidopa (LD/CD, 50 : 50 mg kg−1, i.p.). Locomotor activity was assessed 1 h later. All the COMT inhibitors (COMTI), with the exception of QO IA, markedly potentiated LD/CD reversal of reserpine‐induced akinesia. Similar results were obtained when the COMTI were coadministered with LD/CD. The effect of compound QO IIR was dose‐dependent (7.5–30 mg kg−1, i.p.). The COMTI (30 mg kg−1, i.p.) potentiated LD/CD reversal of both catalepsy and hypothermia of reserpinized mice. QO IIR, nitecapone and Ro‐41‐0960 (30 mg kg−1, i.p.) reduced striatal 3‐methyl‐DOPA (3‐OMD) levels and increased dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels. Compound QO IA was devoid of any effect on striatal amine levels. In contrast to the other inhibitors, Ro‐41‐0961 reduced HVA levels as well. The effect of QO IIR on striatal amine levels was dose‐dependent (7.5–60 mg kg−1, i.p.) These results suggest that the new compound QO IIR is an effective peripherally acting COMT inhibitor in vivo.

Synthesis, pharmacological study and docking calculations of new benzo[f]coumarin derivatives as dual inhibitors of enzymatic systems involved in neurodegenerative diseases

BACKGROUND Due to the complex etiology of neurodegenerative diseases, there is growing interest in multitarget drugs. In this study we synthesized and evaluated a new series of compounds, with benzo[f]coumarin structure, as potential inhibitors of MAO-A, MAO-B, AChE and BuChE. RESULTS In vitro studies show that most of the studied compounds inhibited the activity of MAO-B in the nano- to micro-molar range. 3-(3´-methoxyphenyl)benzo[f]coumarin is the most active compound with an IC50 value against MAO-B of 2.44 nM. Most of the derivatives exhibited an important selectivity profile against the MAO-B isoform. Some of them also acted as in vitro inhibitors of BuChE, with 3-(2´-hydroxyphenyl)benzo[f]coumarin being the most active with an IC50 value of 1.13 µM. In addition, a theoretical study of the physicochemical properties of the new compounds, as well as a docking study in both MAO isoforms, were carried out. Important structure-activity relationships were obtained. CONCLUSION Important preliminary structure-activity relationships were concluded from the experimental results. These results encourage us to further explore the potential of this chemical family as potential drug candidates for the treatment of Alzheimers disease.

Butyrophenone analogues in the carbazole series: synthesis and determination of affinities at D2 and 5-HT2A receptors.

We describe a practical and efficient route for synthesis of 2-aminomethyl-1,2,3,9-tetrahydro-4H-carbazol-4-ones using an effective Fisher indole methodology. The most active compounds, 4b (QF 2003B) and 4c (QF 2004B), with pKi (5-HT2A/D2) ratio of 1.28 show an antipsychotic profile according to Meltzers classification.

Comparison of the antidepressive effects of trans-resveratrol and 5-methoxy-7H-dibenzo[de,h]quinolin-7-one.

In this study we evaluate the in vivo antidepressant effect of a natural phenolic compound, trans-resveratrol, and a synthetic derivative from Menispermum dauricum DC (Menispermaceae) 5-methoxy-7H-dibenzo[de,h]quinolin-7- one known as 5-methoxyoxoisoaporphine (OXO 4). The antidepressant-like effect of trans-resveratrol and OXO 4 were evaluated through a Forced Swimming Test (FST), and they were compared with reference antidepressants: imipramine, desipramine, nomifensine, bupropion, nisoxetine, citalopram and moclobemide. Trans-resveratrol (10 mg/kg, intraperitoneally i.p. significantly decreased the immobility time in mouse model of despair test (69.03 ± 8.74 sec) p<0.05, as well as OXO 4 (1mg/kg, i.p. (60.92 ± 11.37 sec); p<0.05. We also evaluate the OXO 4 at 15, 30 and 45 min. affording the mayor reduction at 30 minutes after the administration. Thus, our results suggest that OXO 4 has a great antidepressant effect non-reported for this type of isoquinoline alkaloids. The pharmaceutical use of OXO 4 in the treatment of depressive disorders is a therapeutic alternative to be studied.