José L. Castro

Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

Inhibitory neurotransmission in the brain is largely mediated by GABAA receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (α1 H101R) with a diazepam-insensitive α1 subtype and a selective BZ site ligand, L-838,417, to explore GABAA receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the α1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABAA receptor subtypes in distinct neuronal circuits.

2-Aryl tryptamines: selective high-affinity antagonists for the h5-HT2A receptor

A series of 2-aryl tryptamines have been identified as high-affinity h5-HT2A antagonists. Structure-activity relationship studies have shown that h5-HT2A affinity can be attained via modifications to the tryptamine side chain and that selectivity over h5-HT2C and hD2 receptors can be controlled by suitable C-2 aryl groups.

Population density in Podarcis lilfordi (Squamata, Lacertidae), a lizard species endemic to small islets in the Balearic Islands (Spain)

The Balearic lizard, Podarcis lilfordi , is present in 43 insular populations in the Cabrera archipelago and around the coasts of Mallorca and Menorca islands (Spain). We studied lizard densities over the entire range of distribution, analyzing observed differences of density in relation to island area, habitat diversity, availability of resources, presence of predators, competitors and human disturbances. The density of the Balearic lizard varies from less than 35 to almost 8000 lizards ha –1 , with an average of around 1500 lizards ha –1 . In some very small islets we detected no more than 10 individuals. Using a subsample of nine coastal islets (Menorca) we did not find any significant correlation between ground arthropod biomass and lizard density. The combination of island area and its maximal altitude, its so-called biotic capacity, was also uncorrelated with lizard density. In addition, neither degree of island accessibility nor presence/absence of seagull breeding colonies, were able to explain lizard densities. Islands without ship rats ( Rattus rattus ) showed a significantly higher lizard density, but islands in which rat eradication programs were launched during the study period, showed lower densities than those with rats but no eradication actions. Genetic variability was significantly higher on bigger lizard populations, lacking a correlation with lizard densities. No single independent variable can explain density differences among populations under study. Our results are discussed in the light of available hypotheses on factors affecting population densities.

Solid-phase synthesis of cyclic sulfonamides employing a ring-closing metathesis–cleavage strategy

Abstract Ring-closing olefin metathesis using the Grubbs catalyst was applied to the cyclisative release of resin-bound sulfonamides. Flexible linkers apparently facilitated the cyclisation–cleavage, allowing a number of novel cyclic sulfonamides to be prepared in good yields using catalytic amounts of the Grubbs catalyst.

γ-Secretase: characterization and implication for Alzheimer disease therapy

gamma-Secretase is a membrane-bound protease that cleaves within the transmembrane region of amyloid precursor protein to generate the C-termini of the Abeta peptides which are believed to play a central role in the neuropathology of Alzheimers disease. An in vitro gamma-secretase assay using a recombinant substrate C100Flag has been developed to facilitate the characterization and identification of this enigmatic protease. Biochemical studies establish that gamma-secretase activity is catalyzed by a PS1-containing macromolecular complex. Moreover, the fact that the photoreactive active gamma-secretase inhibitor directed to the active site labels PS1 suggests that PS1 contains the active site of the protease. Presenilin/gamma-secretase as a potential target for AD therapy and its role in regulated intramembrane proteolysis are discussed.

Stereoselective Construction of the Tricyclic Core of Neoliacinic Acid

The tricyclic core of the plant-derived sesquiterpene natural product neoliacinic acid was synthesized using a novel synthetic strategy. The pivotal synthetic transformations are construction of the key bicyclic ether-bridged intermediate by sequential deployment of metal carbenoid C-H insertion and ylide-forming reactions and installation of the lactone portion of neoliacinic acid by an acid-catalyzed intramolecular ring-opening reaction of an epoxide with a carboxylic acid.

Synthesis and γ-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres

Two new APP substrate-based hydroxyethylene isosteres (AT and VI) were prepared and their dipeptide conjugates shown not to inhibit the γ-secretase-mediated formation of either Aβ1-40 or Aβ1-42. The FG isostere and a des-hydroxy hydroxyethylene isostere also gave inactive compounds. Conversely, a number of compounds containing the intact substrate-unrelated Phe-Phe (FF) hydroxyethylene isostere were shown to be potent inhibitors (ED50=14–732 nM). These results show that the factors governing the substrate-based design of γ-secretase inhibitors are more complicated than first thought.

Rapid analogue synthesis of trisubstituted triazolo[4,3-b]pyridazines

A rapid analogue synthesis of biologically active 3,6,7-trisubstituted 1,2,4-triazolo[4,3-b]pyridazines was devised to give easy and selective variation of the three substituents through combinations of silicon-directed anion formation, palladium-catalysed couplings and SNAr displacements.

2,7-Diazabicyclo[3.3.0]octanes as novel h5-HT1D receptor agonists

The conformational restriction of a (benzylamino)methyl substituted pyrrolidine to form 2,7-diazabicyclo[3.3.0]octanes has led to a series of compounds with high affinity at the h5-HT1D receptor as well as dramatically increased concentrations in the hepatic portal vein following oral administration.

Asymmetric synthesis of the northern segment of ephedradine C. A novel dihydrobenzo[b]furan formation

An asymmetric synthesis of the dihydrobenzo[b]furan segment of ephedradine C has been achieved utilising a chiral oxazolidinone in an aldol reaction to form a β-hydroxy ester, followed by a novel debenzylation and concomitant intramolecular cyclisation with iodotrimethylsilane as key steps. An asymmetric Michael reaction with a homochiral lithium amide was used to form the third and final chiral centre.