Research and development of κ opioid receptor agonists and δ opioid receptor agonists.

Delta opioid delta receptor (DOP) agonists were expected to be analgesics and many researchers tried to develop the SNC80 derivatives. However, the derivatives were dropped at the stage of early clinical trials because of undesirable side effects and weak analgesia. On the other hand, DOP agonists have been proposed as attractive candidates for the novel psychotropic drugs. We recently succeeded in synthesizing a novel selective DOP agonist KNT-127. KNT-127 produced neither catalepsy nor convulsive effects. We have demonstrated that KNT-127 has potent anxiolytic-like effect in rat models of innate anxiety. This anxiolytic-like effect was independent from known adverse effect of benzodiazepine, such as memory impairment, motor coordination deficits, and ethanol interactions. We have also demonstrated that KNT-127 showed potent and rapid antidepressant-like effects in rat models of depression. This antidepressant-like effect was independent from known adverse effect of selective serotonin reuptake inhibitor (SSRI), such as digestive symptoms. Therefore, we propose that DOP should be considered as an attractive target for the development of novel psychotropic drugs, without producing the adverse effects associated with benzodiazepine anxiolytics and SSRI antidepressants. Very recently, we developed another delta agonist NC-2800 with a different structure. NC-2800 is now in the preclinical stage using the CiCLE fund supported by AMED (Japanese Agency for Medical Research and Development).

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