Virgili Pérez

Relevance of benzyloxy group in 2-indolyl methylamines in the selective MAO-B inhibition.

Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition. A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy‐indolyl methylamines, N‐(2‐propynyl)‐2‐(5‐benzyloxyindol)methylamine FA‐73 was the most potent MAO‐B ‘suicide’ inhibitor studied. The Ki values for MAO‐A and MAO‐B were 800±60 and 0.75±0.15 nM, respectively. These data represent a selectivity value of 1066 for MAO‐B, being 48 times more selective than L‐deprenyl (Ki values of 376±0.032 and 16.8±0.1 nM for MAO A and MAO‐B, respectively). The IC50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150±8 μM for FA‐73 and 68±10 μM for L‐deprenyl whereas in human caudate tissue the IC50 values were 0.36±0.015 μM for FA‐73 and 0.10±0.007 μM for L‐deprenyl. Moreover, mouse brain MAO‐B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg−1 adminstration, MAO‐A activity was not affected. These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non‐amphetamine‐like MAO‐B inhibitors with therapeutic potential for the treatment of neurological disorders.

Preclinical and clinical characterization of the selective 5‐HT1A receptor antagonist DU‐125530 for antidepressant treatment

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5‐HT reuptake inhibitors (SSRI) and other 5‐HT‐enhancing drugs is compromised by a negative feedback mechanism involving 5‐HT1A autoreceptor activation by the excess 5‐HT produced by these drugs in the somatodendritic region of 5‐HT neurones. 5‐HT1A receptor antagonists augment antidepressant‐like effects in rodents by preventing this negative feedback, and the mixed β‐adrenoceptor/5‐HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5‐HT1A autoreceptors. However, it is unclear whether 5‐HT1A receptor antagonists not discriminating between pre‐ and post‐synaptic 5‐HT1A receptors would be clinically effective.

Estradiol facilitates neurite maintenance by a Src/Ras/ERK signalling pathway

Different reports suggest the estrogens are involved in neuritic outgrowth, maintenance of dendritic morphology and spine formation in the CNS. However, the molecular mechanisms regulated by estrogens on neuronal integrity are not fully understood. We have addressed the relationship between 17beta-estradiol-dependent ERK pathway stimulation and the maintenance of neuritic morphology in cerebellar granule cell cultures (CGC). We report that 17beta-estradiol clearly activates ERK phosphorylation in CGC cultured in low potassium via ERalpha localized in the plasma membrane and without the activation of the insulin-like growth factor-I receptor. 17beta-estradiol activates the ERK pathway through Ras-dependent Src kinase activity. A concomitant activation of the cAMP-response element-binding protein (CREB) is observed. Moreover, we demonstrate that 17beta-estradiol-mediated ERK activation is involved in the maintenance of neuritic arborisation and neuronal morphology in proapoptotic conditions.

The novel type B MAO inhibitor PF9601N enhances the duration of L-DOPA-induced contralateral turning in 6-hydroxydopamine lesioned rats.

Summary. The present study examined the effect of the highly potent and selective MAO B inhibitor PF9601N on L-DOPA-induced rotational behavior in unilateral nigrostriatal 6-hydroxydopamine lesioned rats. Three doses of PF9601N (20, 40 and 60 mg/kg) were administered 30 min before an injection of L-DOPA (25 mg/kg), and both contralateral and ipsilateral rotational behavior was measured. In addition, we also studied the effect produced by another MAO B inhibitor, deprenyl (20 mg/kg), the MAO A inhibitor, clorgyline (20 mg/kg), and the dopamine reuptake inhibitor, GBR2909 (7.5 mg/kg) on L-DOPA-induced rotational behavior. The results showed that PF9601N plus L-DOPA significantly enhanced the duration of contralateral rotational behavior with respect to L-DOPA plus vehicle in a dose-related manner. At the dose of 40 and 60 mg/kg, PF9601N produced significantly more overall contralateral turning than L-DOPA plus vehicle, and at the dose of 60 mg/kg, PF9601N produced significantly more turning behavior than L-DOPA plus deprenyl. These results suggest that PF9601N may be used as a novel tool in the treatment of Parkinsons disease.

Protective effect of N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine (PF 9601N), a novel MAO-B inhibitor, on dopamine-lesioned PC12 cultured cells

Oxidative stress may play a role in the pathogenesis of Parkinsons disease. We have standardised a new model of dopaminergic‐cell toxicity that uses dopamine, which is able to generate free radicals, as a toxin. The effect of this catecholamine on cell viability (MTT staining) was dose‐dependent, reaching 65% of cell loss at a dopamine concentration of 300 μm. In this model, the protective effect of a novel MAO‐B inhibitor, N‐(2‐propynyl)‐2‐(5‐benzyloxy‐indolyl) methylamine (PF 9601N), was studied and compared with the effect of l‐deprenyl assayed under the same experimental conditions. Whereas PF 9601N (50 μm and 100 μm) showed a significant protective effect, this was not the case with l‐deprenyl. This different behaviour could be explained in terms of difference in antioxidant capacity. The toxicity induced in PC12 cells by 300 μm dopamine was partially reversed by incubating it in the presence of GBR‐12909, a dopamine‐transporter blocker. The results indicated that, besides the intracellular toxicity effect of dopamine, another non‐specific extracellular mechanism could be involved.

Kinetic Studies of N-Allenic Analogues of Tryptamine as Monoamine Oxidase Inhibitors

A series of N‐allenic analogues of tryptamine in which the side chain is located at the 2 position of the indole ring, but which differed in the ring and side‐chain nitrogen substituents, were assayed kinetically as MAO A and MAO B inhibitors.

Interactions between substituted tryptamine analogues, MAO inhibitors and cytochrome P-450

The effects of some MAO inhibitors, N-acetylenic analogues of tryptamine, on rat liver microsomal cytochrome P-450 (cyt P-450) have been investigated. All the compounds tested interacted with cyt P-450 with Ks values ranging between 14 and 358 microM (clorgyline Ks = 10.5 microM). Compounds with a tertiary amine and those possessing a secondary amine group in the acetylenic side chain exhibited type I and type II difference spectra, respectively. Aniline hydroxylase activity was inhibited irreversibly and in a time-dependent fashion by all compounds tested with IC50 ranging between 7 x 10(-5) and 7 x 10(-3) M (clorgyline 10(-4) M).

New2-[(5-Methoxy-1-Methylindolyl)]-Alkylamine Derivatives: the Effect of Branching and Elongation of the Side Chain on Mao Inhibition

A novel series of previously synthesised 2-[(5-methoxy-1-methylindolyl)]alkylamine derivatives were irreversible and time-dependent mechanism-based inhibitors of MAO. The effect of branching and elongation of the side chain was evaluated on the inhibitory potency towards MAO-A and MAO-B activities. The KI of the reversible step and the kinact of the irreversible one were determined in each case. The results obtained lead to the conclusion that neither the elongation nor the branching of the side chain improve the potency of the compounds as MAO inhibitors.

Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

Interactions of monoamine oxidase inhibitors, N-acetylenic analogues of tryptamine, with rat liver microsomal cytochrome P450.

Abstract— Interactions between some novel and potent monoamine oxidase inhibitors (MAOIs), acetylenic analogues of tryptamine, and rat liver microsomal cytochrome P450 (P450) as evidenced by visible spectra analysis were analysed. Compounds with a secondary aliphatic amine moiety throughout induced type II difference spectra and exhibited the highest affinity for P450, whereas tertiary amines induced type I spectral changes and showed diminished affinity. P450 dependent aniline hydroxylase activity was inhibited by all compounds in an irreversible time‐dependent manner. Only tertiary aliphatic amines constituted the substrate for P450‐dependent N‐demethylase activity, with comparable kinetic parameters. The N‐demethylated metabolites were identified by thin‐layer chromatography and mass‐spectrometric analyses. These findings describe the role of P450‐dependent microsomal mono‐oxygenase systems in the metabolism of some MAOI acetylenic tryptamine derivatives and the possible hepatic contribution to adverse interactions between MAOIs, endobiotics and sympathomimetic compounds.