Edwin G. Pérez

An intermolecular palladium-catalyzed diamination of unactivated alkenes.

(b) Reaction with 2 equivalents of saccharin. (c) n.d. = not determined, less than 5 % conversion. (d) Enamide product. (e) In the presence of 2 equivalents of NaOAc. (f) Yield of isolated product in parentheses. (g) Reaction at room temperature. (h) With 5 mol % catalyst. Tos = tolu- ene-4-sulfonyl.

Why is quercetin a better antioxidant than taxifolin? Theoretical study of mechanisms involving activated forms

The stronger antioxidant capacity of the flavonoid quercetin (Q) compared with taxifolin (dihydroquercetin, T) has been the subject of previous experimental and theoretical studies. Theoretical work has focused on the analysis of hydrogen bond dissociation energies (BDE) of the OH phenolic groups, but consider mechanisms that only involve the transfer of one hydrogen atom. In the present work we consider other mechanisms involving a second hydrogen transfer in reactions with free radicals. The relative stability of the radicals formed after the first hydrogen transfer reaction is considered in discussing the antioxidant activity of Q and T. In terms of global and local theoretical reactivity descriptors, we propose that the radical arising from Q should be more persistent in the environment and with the capability to react with a second radical by hydrogen transfer, proton transfer and electron transfer mechanisms. These mechanisms could be responsible of the stronger antioxidant capacity of Q.

Regioselective Intermolecular Diamination and Aminooxygenation of Alkenes with Saccharin

Palladium catalysis enables the regioselective difunctionalization of alkenes using saccharin as the nitrogen source in the initial step of aminopalladation. Depending on the reaction conditions, diamination or aminooxygenation pathways can be accessed using hypervalent iodine reagents as the terminal oxidants. The aminooxygenation of allylic ethers originates from an unprecedented ambident behavior of saccharin. The participating palladium catalysts contain a palladium-saccharide unit. Two representative complexes of this type could be isolated and characterized.

The Antinociceptive and Antiinflammatory Properties of 3-furan-2-yl-N-p-tolyl-acrylamide, a Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors in Mice

BACKGROUND:Positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy of agonists without directly acting on the orthosteric binding sites. In this regard, selective &agr;7 nicotinic acetylcholine receptor type II PAMs display antinociceptive activity in rodent chronic inflammatory and neuropathic pain models. This study investigates whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a new putative &agr;7-selective type II PAM, attenuates experimental inflammatory and neuropathic pains in mice. METHODS:We tested the activity of PAM-2 after intraperitoneal administration in 3 pain assays: the carrageenan-induced inflammatory pain, the complete Freund adjuvant–induced inflammatory pain, and the chronic constriction injury–induced neuropathic pain in mice. We also tested whether PAM-2 enhanced the effects of the selective &agr;7 agonist choline in the mouse carrageenan test given intrathecally. Because the experience of pain has both sensory and affective dimensions, we also evaluated the effects of PAM-2 on acetic acid–induced aversion by using the conditioned place aversion test. RESULTS:We observed that systemic administration of PAM-2 significantly reversed mechanical allodynia and thermal hyperalgesia in inflammatory and neuropathic pain models in a dose- and time-dependent manner without motor impairment. In addition, by attenuating the paw edema in inflammatory models, PAM-2 showed antiinflammatory properties. The antinociceptive effect of PAM-2 was inhibited by the selective competitive antagonist methyllycaconitine, indicating that the effect is mediated by &agr;7 nicotinic acetylcholine receptors. Furthermore, PAM-2 enhanced the antiallodynic and antiinflammatory effects of choline, a selective &agr;7 agonist, in the mouse carrageenan test. PAM-2 was also effective in reducing acetic acid–induced aversion in the conditioned place aversion assay. CONCLUSIONS:These findings suggest that the administration of PAM-2, a new &agr;7-selective type II PAM, reduces the neuropathic and inflammatory pain sensory and affective behaviors in the mouse. Thus, this drug may have therapeutic applications in the treatment and management of chronic pain.

Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor

Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.

Synthesis and antiplasmodial activity of some 1-azabenzanthrone derivatives

Some synthetic 1-azabenzanthrones (7H-dibenzo[de,h]quinolin-7-ones) are weakly to moderately cytotoxic, suggesting that they might also show antiparasitic activity. We have now tested a small collection of these compounds in vitro against a chloroquine-resistant Plasmodium falciparum strain, comparing their cytotoxicity against normal human fibroblasts. Our results indicate that 5-methoxy-1-azabenzanthrone and its 2,3-dihydro analogue have low micromolar antiplasmodial activities and showed more than 10-fold selectivity against the parasite, indicating that the dihydro compound, in particular, might serve as a lead compound for further development.

Synthesis and evaluation of N1-alkylindole-3-ylalkylammonium compounds as nicotinic acetylcholine receptor ligands

In this study thirty-three novel indole derivatives were designed and synthesized based on the structure of deformylflustrabromine B (1), a metabolite isolated from the marine bryozoan Flustra foliacea L. The syntheses were carried out using standard methodologies and in good yields. The molecules were tested for their affinities for the α4β2(∗), α3β4(∗), α7(∗) and (α1)(2)β1γδ nicotinic acetylcholine receptor (nAChR) subtypes. Binding assays showed that, among these ligands, compound 7c exhibited the highest affinity with K(i)=136.1, 93.9 and 862.4nM for the α4β2(∗), α3β4(∗), and α7(∗) nAChRs subtypes, respectively. These results indicated that the indole core might be a useful scaffold for the development of new potent and selective nAChR ligands.

Copper‐Catalyzed Intermolecular Aminooxygenation of Styrenes using N‐Fluorobenzenesulfonimide and Simple Alcohols

The mild and fast copper‐catalyzed radical and regioselective aminoalkoxylation of styrenes by using N‐fluorobenzenesulfonimide and simple alcohols as nitrogen and alkoxy sources, respectively, was investigated. The aminoalkoxylated products obtained could be used in the synthesis of new compounds with possible activity as neurotransmitter receptor ligands.

Further mulinane diterpenoids from Azorella compacta

The chemical study of a dichloromethane extract from Azorella compacta was directed to the isolation of characteristic mulinane and azorellane diterpenoids in order to determine their gastroprotective activity.

Dual effects of a 2-benzylquinuclidinium derivative on α7-containing nicotinic acetylcholine receptors in rat hippocampal interneurons

Nicotinic acetylcholine receptors (nAChRs) are widely distributed in the brain. Particularly α7-containing nAChRs, associated with several physiological roles and pathologies, are one of the most abundant. Here, we studied 2-(4-hexyloxybenzyl)-1-methylquinuclidin-1-ium iodide (designated as 8d), on ion currents elicited by choline, ICh, (Ch, a selective agonist for α7-containing nAChRs), recorded in interneurons from the stratum radiatum of the rat hippocampal CA1 region by using the whole-cell voltage-clamp technique. The 8d-concentration/Ch-response relationship exhibited high and low inhibitory affinities for α7-containing nAChRs, with IC50 values of 0.59 and 6.80 μM, respectively. Interestingly, 8d in a range of 3-10 μM exerted opposite effects: a short early potentiation and a long late inhibition of the ICh; and 8d alone elicited a non-decaying inward current. Furthermore, potentiation and inhibition of the ICh by 8d depended on the membrane potential, both being stronger at -20 than at -70 mV; indicating that 8d interacts with at least two sites into the ion channel/receptor complex: one for potentiating and another for inhibiting the α7-containing nAChRs. These results suggest that 8d may act as agonist, antagonist and positive modulator of α7-containing nAChRs in hippocampal interneurons.