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Roth added: "My UNC lab spent more than a year characterizing the pharmacology and drug-like properties of the molecules before we could hand them off for animal testing in the Dubocovich lab at UB. We were all excited to see that the new compounds Brian and I had discovered had interesting properties in mice." Fifteen-year search
The new research caps what Dubocovich says has been her 15-year search to discover MT1 ligands.
"Ever since we demonstrated that melatonin's effect of resetting biological clocks in vivo circadian models occurs through actions at the MT1 receptors, we have focused through various collaborations on searching for ligands that would better fit the human melatonin receptor," she said. "Our hope has always been to find selective MT1 -type molecules, either one that works to modulate circadian rhythms responses as with melatonin or its opposite as with the molecules discovered in this study."
The ultimate goal, she said, was always to develop drugs that could address all the disorders that disrupted circadian rhythms can cause. "So," she noted, "when Brian Schoichet called to ask about our interest in testing in our circadian mouse models the novel molecules they had identified from his ultra-large library of over 150 million compounds, we were eager to collaborate!"
The availability of the UCSF vast virtual library was a critical aspect of the research. Dubocovich described it as a "gold mine" of millions of molecules with distinct shapes, many of which have never been synthesized or seen in nature, and all of them available for mining and "docking" (fitting) into the pocket of the targeted receptor. The team advanced the research directly from discovery of these molecules to the assessment of their ability to mimic or oppose the effect of melatonin, to in vivo demonstrations of how these molecules impact the animals' circadian function.
The team found it especially interesting that the two molecules discovered in this study generate two distinct and opposite mouse circadian responses that are dependent on clock time and the environmental light conditions that the animals experience.
In the experiments where the onset of dark is advanced (known as reentrainment or the jet lag model) the molecules slow this reentrainment or adjustment, an effect opposite to that of melatonin. However, when mice were exposed to constant dark, the two molecules demonstrate an effect identical to that of melatonin.
"This could be potentially useful to entrain rhythms to the 24-hour day in populations removed from natural light/dark exposure, including the blind as well as some shift workers, submarine workers or those working in extreme environments, such as polar explorers," she said. Jet lag and chronopharmocology
"When the body is exposed to an abrupt change in the light/dark cycle, like what we experience when we travel across continents, there isn't sufficient time for the biological clock to adjust upon reaching the destination," Dubocovich explained.
"Giving these new molecules at the appropriate clock time under a light/dark cycle would allow us to decelerate our ability to adjust to the new environment, potentially providing a treatment for certain types of jet lag and, more importantly, addressing other conditions affected by circadian rhythm disruptions, such as shift work, sleep disorders and depression," she said.
This finding reinforces the increased interest in chronopharmacology, the premise of which is that pharmaceuticals given at the time when a patient's biological clock is ready to receive them - given conditions of a precise time of day and environmental lighting - will produce a more effective outcome.
Dubocovich said the next step will be to identify the molecular and signaling pathways that translate the response exerted by these molecules from the time they interact with the receptors in the biological clock to the ultimate circadian behavior expressed in a mouse or human. Source:
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