Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression.

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.

Familiar size affects the perceived size and distance of real objects even with binocular vision.

Although the familiar size of real-world objects affects size and distance perception, evidence is mixed about whether this is the case when oculomotor cues are available. We examined the familiar size effect (FSE) on both size and distance perception for real objects under two viewing conditions with full or restricted oculomotor cues (binocular viewing, which provides vergence and accommodation cues, and monocular viewing through a 1-mm pinhole, which removes those cues). Familiar objects (a playing die versus a Rubik's cube) were manufactured in their typical (1.6-cm die and 5.7-cm Rubik's cube) and reverse (5.7-cm die and 1.6-cm Rubik's cube) sizes and shown at two distances (25 cm versus 91 cm) in isolation. Small near and large far objects subtended equal retinal angles. Participants provided manual estimates of perceived size and distance. For every combination of size and distance, Rubik's cubes were perceived as larger and farther than the dice, even during binocular viewing at near distances (<1 meter), when oculomotor cues are particularly strong. For size perception but not distance perception, the familiar size effect was significantly stronger under monocular pinhole viewing than binocular viewing. These results suggest that (1) familiar size affects the accuracy of perception, not just the speed; (2) the effect occurs even when oculomotor cues are available; and (3) size and distance perception are not perfectly yoked.