The costs of avoiding matings in the dung fly Sepsis cynipsea

Mating is generally assumed to carry costs, particularly forfemales, which have to be traded off against each other andagainst the fitness benefits of mating. To understand any particularmating system and the evolution of sexual conflict, these costshave to be evaluated. Female dung flies, Sepsis cynipsea (Diptera:Sepsidae), typically attempt to dislodge mounted males by vigorousshaking. Such female reluctance to mate can only evolve if the cost of avoiding matings does not exceed the cost of copulation.We investigated female precopulatory costs of assessing andrejecting males in terms of increased predation, wing injuries,and (indirectly) energetics, all ultimately affecting mortality,and compared them to the costs of copulation assessed in thisand a companion study. Females housed with a male had lower survivorship than females housed with another female. This waslargely due to the costs of copulation rather than presumedenergetic costs of avoiding males, which were minor. Male harassmentaugmented female wing injuries, which accumulate with age inthe field and laboratory, but in laboratory experiments usingone common predator, wing injuries did not increase the susceptibility of S. cynipsea to predation, nor did their mating behavior perse. Instead, predation was highest and survivorship lowestin all-male groups, probably because males are more activein search of females and harass each other. Overall, the precopulatorycosts of mate assessment and rejection were low relative tothe costs of copulating, explaining female reluctance behavior in this and possibly other species.     

Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache

Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu₂ receptor. The hydroxyacetophenone scaffold is a second series of mGlu₂ PAMs we have identified. This series of molecules are potent mGlu₂ potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.