Synthesis of various pyrazinone ring-containing opioid mimetics and studies on their structure-activity relationship

摘要

Previously we demonstrated that the pyrazinone ring-containing opioid mimetic 3,6-bis[3'-Dmt-aminopropyl]-5-methyl-2(lH)-pyrazinone(I)exhibited high mu-opioid receptor affinity(Ki = 0.042 nM)and less 8-opioid receptor affinity(Ki =13.2 nM)with moderate selectivity(Ki delta/Ki mu = 307).3-[4'-Dmt-ammobutyl]-6-[3'-Dmt-arninopropyl]-5-methyl-2(1H)-pyrazinone(II)bound to u-opioid receptors with high affinity(Ki = 0.021 nM)and to 8-opioid receptors(Ki = 31.9 nM)with a high selectivity(Ki delta/Ki mu = 1,519).Both compounds exhibited considerably potent antinociceptive activity in mice following intracerebroventricular(i.e.v.),subcutaneous(s.c.)and per oral(p.o.)administration.These results exhibited that pyrazinone ring containing opioid mimetics(I,II)can pass through the epithelium of the gastrointestinal tract and the blood brain barrier(BBB).Therefore,our attention was focused to synthesis of various 3-[Dmt-aminoalkyl]-6-[Dmt-aminoalkyl]-5-methy-2(lH)-pyrazinone(III-VIII:see Figure 1)and studies on the relationship between the structure of opioid mimetics and their oipid receptor binding affinity.