Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators

We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3 mg/kg, q.d.).     

Understanding how environmental factors influence reproductive aspects of wild myomorphic and hystricomorphic rodents

Myomorphic and hystricomorphic rodents are vital for maintaining various ecosystems around the planet. This review enables a better understanding of how these rodents respond to environmental factors and adapt to climate adversities. Innumerable factors, such as photoperiod, rainfall, and temperature, can impair or contribute to the quality of rodent reproductive parameters. Prolonged animal exposure to high ambient temperatures alters thermoregulation mechanisms and causes testicular and ovarian tissue degeneration and hormonal deregulation. Photoperiod influences the biological circannual rhythm and reproductive cycles of rodents because it strongly regulates melatonin secretion by the pineal gland, which modulates gonadotropic hormone secretion. Rainfall quantity directly regulates the abundance of fruits in an ecosystem, which modulates the reproductive seasonality of species which are most dependent on a seasonal fruit-based diet. Species with a more diversified fruit diet have smaller reproductive seasonality. As such, habitats are chosen by animals for various reasons, including the availability of food, sexual partners, intra-and inter-specific competition, and predation. This knowledge allows us to monitor and establish management plans to aid in conservation strategies for wild rodent species.     

Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma

Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed.We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development.     

Seasonal dynamics of the fish parasite Neoplagioporus ayu (Digenea) in its definitive host, Plecoglossus altivelis, in the Chikugo River, Kyushu, Japan

Seasonal dynamics of the fish parasite Neoplagioporus ayu (Digenea; Opecoelidae; Plagioporinae) in its definitive host, the ayu Plecoglossus altivelis, in the Chikugo River, Kyushu, Japan, was examined. Natural ayu are amphidromous. In the upper Chikugo River, ayu fry raised in hatcheries are released into the river every spring because the migration of ayu is completely blocked by a dam that has no fish-pass channel. Ayu collected in April 2003 (within 1 month after release) harbored no N. ayu, but the prevalence of N. ayu rose to about 80% in May. The prevalence, abundance, and maturity of N. ayu were maintained at high levels from June to September. These finding indicate that the life cycle of N. ayu is completed in a freshwater area, although its intermediate hosts have not yet been identified despite the intense examination of invertebrates.