Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller-Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.

In 1949 Barklay, Haas, Huggett, King & Rowley recorded the fructose and non-fructose reducing substances in the amniotic and allantoic fluids and the blood of the sheep foetus. This paper records experiments designed to ascertain the origin of the blood fructose of the foetal sheep.t In the 1949 paper Barklay et al. recorded the literature. To the points given there it is worth adding that Bacon & Bell's (1948) isolation and identification of the Seliwanoif-positive ketose as D-fructose was accompanied by proof that the only reducing sugars in the foetal blood were D-glucose and D-fructose. On the other hand, Karvonen (1949a) has shown, using Cole's method (1948), that human cord blood contains no fructose, a result at variance with that of Orr (1924). In 1949 Hitchcock, in a paper marked by pronounced technical accuracy, recorded the levels of fructose and glucose in the foetal and maternal bloods of sheep in the second half of gestation, together with their distribution between corpuscles and plasma. He confirmed more definitely the findings of Barklay et al. (1949) that the fructose of the foetal blood has its highest values in early pregnancy and tends to fall as intrauterine growth proceeds. In addition, he found that glucose traversed the placenta from the mother to the foetus, and he regarded the maternal loss and foetal gain as equivalent. The fructose problem can be posed in the form of three questions. (i) What is the site of the formation of fructose? (ii) What substance gives rise to fructose? (iii) What is its role in the foetus? The experiments in this paper were designed to obtain answers to the first two questions. The relation between the maternal and foetal blood sugars is of primary * Formerly N. V. Winterton. t A preliminary note appeared in Nature (Huggett, Warren & Winterton 1949a) and a communi. cation was given to the 1st International Congress of Biochemistry (Huggett, Warren & Winterton, 1949b). FRUCTOSE IN THE FOETAL SHEEP 259 importance. All evidence, both experimental and clinical (diabetes), goes to show that high maternal blood sugars are accompanied by high foetal blood sugars. Indeed, Passmore & Schlossmann (1938) found that, on injecting glucose into the maternal circulation of goats and sheep, the foetal blood sugar rose to higher levels than the maternal blood sugar. In all their experiments the blood sugar was estimated as glucose. The possibility existed that the apparent excess of foetal glucose over maternal glucose might be due to fructose being formed which was falsely estimated as glucose, the true foetal glucose being actually less than the maternal glucose. In the experiments of this paper the foetal blood glucose and fructose have been determined simultaneously, and they start from the repetition of Passmore & Schlossmann's work on the intravenous injection of glucose into the maternal circulation. METHODS These were essentially the same as described in Barklay et al. (1949). Welsh ewes ofknown conceptual date were received in the laboratory 1 or 2 days before the ex...

It hs been suggested that metabotropic glutamate receptor subtype 5 (mGluR5) play a role in the expression of anxiety, based on anxiolytic-like effects of the selective mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) in rodent models of anxiety, including stress-induced hyperthermia (SIH). To examine the suggested role of mGlu5 receptors in the expression of anxiety, we examined the stress response in mice lacking mGluR5 in several variations of the SIH procedure. In this paradigm, stress causes a mild increase in body temperature that can be blocked by known anxiolytic agents. Three procedures were employed: classical SIH using rectal-probe measurement of body temperature, and radiotelemetric measurement of body temperature in response to either saline injection or to the introduction of an intruder into the home cage. In all three procedures the mGluR5-knockout mice displayed a significant attenuation of the hyperthermic response to stress compared to littermate wild-type control mice. To confirm that our observations were likely to be due to the absence of mGluR5 in the knockout mice we also tested the effect of the recently described selective mGluR5 antagonist MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) in both the wild-type and mGluR5 knockout mice. Administration of MTEP in the wild-type mice, but not the mGluR5 knockout mice, attenuated SIH. That the mGluR5 knockout mice displayed an anxiolytic-like phenotype and that the mGluR5 antagonist, MTEP, showed a anxiolytic-like effect only in mice possessing mGluR5 further supports the suggestion that mGluR5 antagonists may be useful in the treatment of anxiety.

A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.