5-Aryl-3-azabicyclo[3.2.0]heptan-6-one ketals, compounds with morphine-like analgesic activity.
A series of 5-aryl-3-azabicyclo[3.2.0] heptan -6-one ketals 6 were synthesized by hydride reduction of 1-aryl-4, 4-dimethoxy-1,2- cyclobutanedicarboximides 5. Imides 5 were obtained as the sole, regioselective products of the [2 + 2] photocycloaddition of 1,1- dimethoxyethylene to 2- arylmaleimides . The m-methoxyphenyl-N-methyl analogue 6a was demethylated to phenol 7 with EtSNa -DMF. Both 6a and 7 were similar to morphine in analgesic potency in rats and mice and showed physiological effects that were identical with those of morphine and that were completely reversed by naloxone. Compound 7 was identical with morphine in its ability to displace [3H]naloxone from homogenates of rat brain minus cerebellum. A molecular mechanics analysis of the m-methoxyphenyl analogue 6a showed that the nitrogen atom, the methoxyphenyl group, and the methoxyl oxygen cis to the phenyl group can be superimposed on the corresponding features of the morphine molecule, and perhaps this accounts for the observed opiate-receptor binding properties of 7.
D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001681:Biological Assay; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D005684:Gait / Q000187:drug effects; D007202:Indicators and Reagents; D009020:Morphine; D009270:Naloxone / Q000378:metabolism; D010146:Pain / Q000503:physiopathology; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D007202:Indicators and Reagents; D011957:Receptors, Opioid; C034565:naloxone receptor; D009270:Naloxone; D009020:Morphine