Characterization of Pyrrolidinyl-hexahydro-pyranopiperazines as a Novel Kappa Opioid Receptor Agonist Scaffold.

The kappa agonist structure-activity relationship around the novel, pyrrolidinyl substituted pyranopiperazine scaffold was developed. More specifically, the dichloroPhenylAcetamide-Pyrrolidinyl-PyranoPiperazine (PAPPP) core A was the focus of our work. The modulation of kappa receptor potency/G-protein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated.

Nalmefene, a mu opioid receptor antagonist/kappa opioid receptor partial agonist, potentiates cocaine motivation but not intake with extended access self-administration in adult male mice.

Unlabelled: The mu opioid receptor antagonist/kappa opioid receptor (KOR) partial agonist nalmefene (NMF), a close structural analog of naltrexone (NTX), has been shown to reduce cocaine reward in preclinical models. Given the greater KOR potency and improved bioavailability compared to NTX, NMF may be a promising pharmacotherapeutic for cocaine use disorder (CUD). Here we examine the effects of NMF pretreatment on chronic daily extended access (4h) cocaine intravenous self-administration (IVSA) in adult male C57Bl/6J mice.

Modulation of cocaine-related behaviors by low doses of the potent KOR agonist nalfurafine in male C57BL6 mice.

Rationale: Agonists of the kappa opioid receptor (KOR) have been shown to block the rewarding effects of drugs of abuse, but with negative side effects. The antipruritic drug nalfurafine, approved in Japan in 2009, is a potent, selective KOR agonist that does not cause significant side effects in humans. Nalfurafine has not been extensively tested for its effect on drug reward and reinforcement in preclinical models.