Structure-Activity Relationship Study of CYM51010, an agonist for the µ-δ Opioid Receptor Heterodimer.

Although opioid analgesics are indispensable in treating pain, these drugs are accompanied by life-threatening side effects. While clinically relevant opioid drugs target the µ opioid receptor (MOR), a heterodimer between the MOR and the δ opioid receptor (DOR) has emerged as another target to develop safer analgesics. Although some heterodimer-preferring agonists have been reported so far, it is still difficult to activate the MOR/DOR heterodimer selectively in the presence of MOR or DOR monomers/homodimers. To gain insights to develop selective agonists for MOR/DOR, herein we prepared analogs of CYM51010, one of the reported heterodimer-preferring agonists, and collected structure-activity relationship information. We found that the ethoxycarbonyl group was needed for the activity for the heterodimer, although this group could be substituted with functional groups with similar sizes, such as an ethoxycarbonyl group. As for the acetylaminophenyl group, not a type of substituent, but rather a substituent located at a specific position (para-position) was essential for the activity. Changing the linker length between the acetylaminophenyl group and the piperidine moiety also had deleterious effects on the activity. On the other hand, the substitution of the acetylamino group with a trifluoroacetylamino group and the substitution of the phenethyl group with a benzyl group diminished the activities for the monomers/homodimers while keeping the activity for MOR/DOR, which enhanced the selectivity. Our findings herein will play an important role in developing selective agonists for MOR/DOR and for elucidating the physiological roles of this heterodimer in analgesic processes and in the establishment of side effects.

[Parent-child relationships and mindfulness].

Psychological approaches such as mindfulness-based stress reduction or mindfulness-based cognitive therapy could be effective for relieving a wide range of psychosocial stresses or frictions between parents and children. Several interventional approaches based on mindfulness have been shown to be useful for improving parent-child relationships not only among healthy families but also among those with difficult psychopathologies. Particularly in the relationships of parents with their children with developmental disorders such as autism or attention-deficit/hyperactivity disorders, these approaches may play an important role in that the motivations of both parents and children could be enhanced because they can actually feel that their mental condition improves through meaningful parent-child interactions that they experience in their daily lives. These approaches are also expected to improve communications between mothers and children through the development of a finely honed sensitivity. One practical example is shown for the mental growth of children by the mindfulness-based dietary education and the secondary effects of this education on the parents. We can also apply these effective methods to the improvement of general interpersonal relationships.