Research On Diarylmethylpiperazine Opioid Receptor Mixed Agonist

Opioid drugs includ natural,semisynthetic and synthetic opioid drugs.Classic opioid analgesics selectively activate MOR with analgesic activity and the advantage of a wide spectrum of anti-pain,but also severe side effects,such as respiratory depression,addiction and tolerance,nausea and vomiting.In order to design the novel analgesic compounds with less or even no side effects,over the past decades,amount of research have been done in opioid analgesics.As evidences of counterbalancing between OR subtype activation have been accumulated recently,such as MOR and DOR,MOR and KOR,OR dual agonists emerged as a potential choice to reduce side effects,but were found only partially effective.DPI-3290 is a mixed MOR/DOR/KOR agonists,which produces analgesic potency between morphine and fentanyl,weakening respiratory depression and dependence relatively and significantly increasing the security.Based on the preliminary study of DPI-3290,achievement of this research is as followed:1.According to the SAR of the DPI-3290 to designed two types of compounds:diarylmethylpipe razine s,diarylmethenep iperidine.2.Exploring the means of synthesis of those compounds.Diarylmethylpiperazines were prepared by the followed four reactions in three steps,with arylaldehyde,chiralpiperazine,1H-Benzotriazole and aryl Grignard to achieve stereoselective reaction.To obtain a synthetic route with high stereoselectivity and high yield,we optimized the scheme,efficiently using the chiral starting materials and saving the time of reaction.Applying the McMurry coupling reaction produced oleficin,then through theacidify,amide,and demethylation to make diarylmethenepiperidines.3.The analgesic effects of KUST 201 and KUST 202 were evaluated by rat/mouse hot-plate test and mouse tail-pinch test The foundation and basis of analgesic effects evaluating was established.