Azabicycloalkanes as analgetics. 3. Structure-activity relationships of 1-phenyl-6-azabicyclo[3.2.1]octanes and absolute stereochemistry of (+)-1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3.2.1]octane and its 7-endo-methyl derivative.
A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (1) has been tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgesic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)8] was established by the x-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivatives [(+)-7] by chemical transformation and CD measurement. Certain structural and stereochemical correlations between these compounds (7 and 8) and other known antagonist-analgetics are discussed.
D000700:Analgesics; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology* / Q000633:toxicity; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D007928:Lethal Dose 50; D008253:Macaca mulatta; D008968:Molecular Conformation; D009269:Nalorphine / Q000494:pharmacology; D009292:Narcotic Antagonists; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013375:Substance Withdrawal Syndrome / Q000139:chemically induced; D019966:Substance-Related Disorders / Q000209:etiology; D014961:X-Ray Diffraction
D000700:Analgesics; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D009292:Narcotic Antagonists; D009269:Nalorphine