beta-Aminophosphonic compounds derived from methyl 1-dimethoxyphosphoryl-2-succinimidocyclohex-3-ene-1-carboxylates

Compounds 3a,b, the [4 + 2] cycloadducts of trimethyl 2-phosphonoacrylate and N-buta-1,3-dienylsuccinimide, have been transformed into various beta -aminophosphonic acid derivatives 4-17 by selective deprotection, epoxidation, dihydroxylation, and oxidative cleavage of the cyclohexenyl C-C double bond

A Practical Synthesis of 1,2-Nitroamines by Michael Addition of N-Nucleophiles to Nitroalkenes

A practical method for the synthesis of alpha-nitroamines by Michael addition of azide to nitroalkene has been developed. This reaction proceeds in high yields under very mild conditions (phase-transfer catalysis) and is found to be general; good yields are obtained with both aryl and alkyl derivatives as well as with 1,1-disubstituted ones

In vitro and in vivo studies of 6,8-(diaryl)imidazo[1,2-a]pyrazin-3(7H)-ones as new antioxidants.

A series of 5-aryl and 3,5-diaryl-2-amino-1,4-pyrazines and the derived imidazopyrazinones has been synthesized to study the chemical oxidative degradation of the bicyclic systems in vitro. Imidazopyrazinones mainly degraded following two independent pathways producing their precursors, namely aminopyrazines, and the corresponding amidopyrazines, respectively. Despite the fact that there is no influence of the substituent of the 3-aryl group on the ratio of the products aminopyrazine/amidopyrazine, diarylimidazopyrazinones and diarylaminopyrazines are good antioxidants in vivo. They protected against microvascular damages in ischemia/reperfusion with similar efficiencies

Recording of the saphenous vein compliance by an ultrasonic echo-tracking device in the dog: effects of S 18149

1. Saphenous vein reactivity was recorded in the anaesthetized dog by use of an ultrasonic echo-tracking device to measure the internal diameter of the vein and to calculate the venous compliance. This method was used to investigate the effects of a new partial α(1)/α(2)-adrenoceptor agonist, S 18149, on the canine saphenous vein in vivo after intravenous (i.v.) or oral administration. 2. Venoconstrictions induced by i.v. or local administration of compounds were evaluated by continuous recording of the internal diameter of the saphenous vein with the echo-tracking method. Venous compliance was calculated in two ways: (1) as the slope of the diameter-pressure curve obtained by increasing the venous pressure with an inflatable cuff and (2) in veins in which pressure was higher than 12 mmHg, pulsatile variations in the venous diameter and venous pressure were detected and used to calculate the pulsatile compliance of the vein. 3. S 18149 administered i.v. at 0.5 μg kg(−1) min(−1) for 10 min induced a decrease in the saphenous vein diameter (−15±3%) and blood flow (−72±6%) associated with an increase in saphenous vein resistance; at the dose used, S 18149 did not modify venous pressure and caused only a weak increase in arterial pressure (+7±2 mmHg). 4. The pulsatile compliance of the saphenous vein averaged 8.65±1.37 mm(2)×100 mmHg(−1) in control dogs and was significantly decreased to 5.13±0.68 mm(2)×100 mmHg(−1) in the same animals after treatment with S 18149 at 100 μg kg(−1) per os (n=10). The saphenous vein compliance calculated with the increased external pressure method averaged 24.90±1.49 μm mmHg(−1) in control dogs and was significantly reduced in the same animals after treatment with S 18149 at 100 μg kg(−1) per os to 9.06±3.42 μm mmHg(−1) (n=5). When constrictions of the vein were induced with increasing doses of (−)-phenylephrine, injected locally at 1, 3 or 6 μg min(−1), only the responses obtained with the lower dose of (−)-phenylephrine were increased in dogs treated with S 18149 100 μg kg(−1) per os (−16±4% versus −4±3%, n=5). 5. These results show that the high resolution echo-tracking device previously used for arterial compliance measurements, allows the detection of pulsatile changes in the canine saphenous vein and thus permits calculation of both the pulsatile and the static compliance of superficial veins in vivo. Using this technique, we have demonstrated that the novel α-adrenoceptor agonist S 18149 constricts the canine saphenous vein in vivo and decreases the saphenous vein compliance after oral administration

Inhibitory and facilitory actions of isocyanine derivatives at human and rat organic cation transporters 1, 2 and 3: A comparison to human α1- and α2-adrenoceptor subtypes

International audienceOrganic cation transporters (OCTs), comprising OCT1, OCT2 and OCT3 subtypes, control absorption and elimination of xenobiotics and endogenous compounds in kidney, liver and placenta. In addition, they ensure "uptake2", low-affinity catecholamine clearance in sympathetically-innervated tissue and the CNS. The prototypical OCT ligand, disprocynium24 (D24), recognises OCT3, but its actions at OCT1 and OCT2 remain unknown. Herein, together with two other isocyanine derivatives (AAC291 and AAC301) and chemically-related adrenergic agents, we evaluated actions of D24 at OCTs, monoamine transporters and alpha(1)- and alpha(2)-adrenoceptors. D24 concentration-dependently suppressed [3H]-1-methyl-4-phenylpyridinium (MPP+) transport at human (h) and rat (r) OCT1, OCT2 and OCT3 in stably transfected HEK293 cells. Interestingly, low concentrations of D24 enhanced transport by h/rOCT2, a substrate-dependent effect suppressed by inhibition of protein kinase C. AAC291 and AAC301 likewise inhibited transport by all classes of h/r OCT and at low concentrations induced even more marked increases in transport by h/rOCT2. Further, by analogy to D24, they displayed antagonist properties at halpha(1A/B/D)-adrenoceptors (Ca2+-flux) and halpha(2A/B/C)-adrenoceptors ([35S]GTPgammaS binding). They were, however, less potent than D24 at serotonin transporters ([3H]citalopram binding) and AAC291 did not bind to dopamine and norepinephrine transporters. The preferential alpha(1B)-adrenoceptor antagonist, AH11110A, the alpha2-adrenoceptor agonist, RWJ52353, and the adrenergic neurotoxin DSP-4 likewise affected [3H]MPP+ transport, in an OCT-subtype and species-dependent manner. In conclusion, D24, other isocyanine congeners and chemically-related adrenergic agents inhibit OCT-mediated [3H]MPP+ transport, and all drugs display significant activity at alpha1- and alpha2-adrenoceptor subtypes, expanding previous reports of promiscuity between pharmacophores recognising alpha-adrenoceptors and OCTs

Protective effect of imidazolopyrazinone antioxidants on ischemia/reperfusion injury.

A series of 2-substituted 3,7-dihydroimidazolo[1,2-a]pyrazine-3-ones has been synthesized and evaluated for their antioxidant activity. Compounds 1-8 are inhibitors of AAPH-induced lipid peroxidation (in vitro) and excellent protectors against microvascular damages in ischemia/reperfusion (in vivo). Hence, the bicyclic structure typical of coelenterazine (luciferin) could be considered as a useful lead in medicinal chemistry

Data from: Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate’s action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5–5.4 μM), except a higher EC50 value for GluA4 flop (0.7 μM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 μM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 μM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 μM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 μM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer’s disease and in Major Depressive Disorder