A Mini Review on Synthesis of Pyrazinoindole: Recent Progress and Perspectives

: The diverse library of biologically active organic compounds is composed majorly of heterocyclic compounds. Nature provides us with a variety of pharmacologically active compounds consisting of N-heterocycle motif such as Noscapine (anti-cancer), Morphine (analgesic), Chelerythrine (antibacterial), etc. which are the elementary structural units of marketed drugs in the present era. One of such “N-heterocyclic” promising building block which has gained attention of chemists is Pyrazinoindoles and the inflating interest in this moiety is a result of the three-fused heterocyclic ring structure subsuming an indolic nucleus in it. Fused-polycyclic structural core is necessary to synthesize for potential multi-functional drugs which is evident from indole (an example of fused five and six-membered ring structure) being an exemplary, established privileged template in medicinal chemistry. In the literature, Pyrazino-fused indoles have been found documented regarding their biological activities and therapeutic uses particularly as antifungal, antibacterial, serotonergic receptor inhibitor, central nervous system depressants, anticonvulsants, antihistaminic, protein kinase C inhibitors, antidepressants and so on. Although various synthesis strategies are available in the literature yet the medical relevance of the Pyrazinoindoles demands the development of versatile and simple novel methodologies. This review features comprehensive overview of the recent developments in synthetic approaches and therapeutic applications of Pyrazinoindoles based scaffolds.

Kainate Receptor-Mediated Depression of Glutamate Release Involves Protein Kinase A in the Cerebellum

Kainate (KA) receptors (KAR) have important modulatory roles of synaptic transmission. In the cerebellum, the action mechanisms of KAR-mediated glutamatergic depression are unknown. We studied these mechanisms by recording evoked excitatory postsynaptic currents (eEPSCs) from cerebellar slices using the whole-cell configuration of the patch-clamp technique. We observed that 3 μM KA decreased the amplitude of eEPSCs and increased the number of failures at the synapses established between parallel fibers (PF) and Purkinje neurons, and the effect was antagonized by NBQX under the condition where AMPA receptors were previously blocked. The inhibition of protein kinase A (PKA) suppressed the effect of KAR activation on eEPSC, and effect was not prevented by protein kinase C inhibitors. Furthermore, in the presence of Pertussis toxin, the depression of glutamate release mediated by KAR activation was prevented, invoking the participation of a Gi/o protein in this modulation. Finally, the KAR-mediated depression of glutamate release was not prevented by blocking calcium-permeable KARs or by treatments that affect calcium release from intracellular stores. We conclude that KARs present at these synapses mediate an inhibition of glutamate release through a mechanism that involves the activation of G-protein and protein kinase A.

Lycopene depresses glutamate release through inhibition of voltage-dependent Ca2+ entry and protein kinase C in rat cerebrocortical nerve terminals

Lycopene is a natural dietary carotenoid that was reported to exhibit a neuroprotective profile. Considering that excitotoxicity and cell death induced by glutamate are involved in many brain disorders, the effect of lycopene on glutamate release in rat cerebrocortical nerve terminals and the possible mechanism involved in such effect was investigated. We observed here that lycopene inhibited 4-aminopyridine (4-AP)-evoked glutamate release and intrasynaptosomal Ca2+ concentration elevation. The inhibitory effect of lycopene on 4-AP-evoked glutamate release was markedly reduced in the presence of the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was insensitive to the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Furthermore, in the presence of the protein kinase C inhibitors GF109203X and Go6976, the action of lycopene on evoked glutamate release was prevented. These results are the first to suggest that lycopene inhibits glutamate release from rat cortical synaptosomes by suppressing presynaptic Ca2+ entry and protein kinase C activity.