Novel cobalt complex inhibitors of mitochondrial calcium uptake.

Reperfusion of the ischaemic myocardium leads to intracellular calcium overload followed by mitochondrial dysfunction, resulting in insufficient energy supply and ultimately myocardial necrosis. Ruthenium red (RR), a potent mitochondrial calcium uptake inhibitor, prevents this disruption to mitochondrial metabolism and improves post reperfusion recovery. This therefore suggested that mitochondrial calcium influx is an attractive target for the treatment of reperfusion injury. However, RR is unsuitable for therapeutic use, so we undertook a search for novel compounds which inhibit mitochondrial calcium uptake. The most potent compounds discovered were simple tris(ethylenediamine) transition metal complexes and dinuclear Co complexes. The structure-activity relationship (SAR) of these small molecules has helped to define the structural requirements for inhibition of calcium transport by outlining the size and charge dependency of the interactive site on the mitochondrial calcium uniporter.

Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy.

The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists.

Laboratory breeding of the European rabbit flea, Spilopsyllus cuniculi (Dale).

A method is described for the laboratory breeding of the rabbit flea in which the immature stages are reared at constant temperature and humidity. Eggs are obtained by confining fleas taken from a rabbit and her nest shortly after parturition with two of her nestlings in an incubator for 24 h. The eggs are transferred to an artificial diet medium on which the immature stages are reared. On average a female flea produces 50 eggs during the first six days post-partum. At 25 degrees C, 95% of eggs hatched at 79% RH and 98% at 84% RH. Most eggs hatched on the third day after laying and hatching was completed by the fourth day. Significantly more fleas of both sexes were obtained when larvae were reared at 25 degrees C on a medium containing powdered 41B rodent diet than on one containing terrier meal. Both diets also contained yeast and dried rabbit blood. There was no significant difference between the numbers of fleas obtained at 79% RH and 84% RH. Significantly more fleas were also obtained when larvae were reared at 27 degrees C, 84% RH, than at 25 degrees C. Female fleas emerged sooner than males at both 27 degrees C and 25 degrees C. Fleas from the laboratory culture were heavier than those from wild nests. Female fleas were heavier than male fleas in both cases.