The structure-action relationship and kinetics of some naloxone and naltrexone derivatives.

The isolated longitudinal muscle preparation (with attached Auerbach plexus) of the guinea pig ileum was used to investigate the structure activity relationship and kinetics of some naloxone and naltrexone derivatives and that of cyclazocine. The agonist used for the investigation of the antagonistic effect of these compounds was 6-azidomorphine (AM). AM was found to be an about 20 times more potent agonist than morphine. In contrast to cyclazocine, which also was found to be approximately 15 times more potent agonist than morphine, naloxone had no demonstrable agonistic activity and naltrexone and the various naloxone and naltrexone derivatives had only insignificant agonistic activity with ED50/Ke ratios ranging from 2,000 to about 120,000. All compounds tested were competitive reversible antagonists of AM. 6-Methylene substitution caused an approximate 50 and 100% increase of the antagonistic activity of naloxone and naltrexone, respectively, and decreased the duration of action of naloxone. 3-Acetate or 3-nicotinate substitution decreased potency and had no effect on the duration of naloxone action. There is a correlation between tachyphylaxis observed on the inhibition of longitudinal muscle contraction and antagonist activity of narcotic agonists.