Kappa-Agonists and Antagonists

As already mentioned, oxidation of C-l methylene of cyclazocine to carbonyl abolishes the antagonist but retains the agonist actions of the parent compound (p. 423). The behavioral and pharmacological effects of the oxidized product ketazocine 26a in the chronic spinal dog were subsequently compared with those of morphine by Martin, and as a result of differences observed, he dubbed the two compounds k- and /a-agonists, respectively.(106) Thus, while morphine induced analgesia, meiosis, bradycardia, hypothermia, and indifference to environmental stimuli, ketazocine produced meiosis, general sedation, and depression of flexor reflexes but did not alter the skin twitch reflex or pulse rates. 

Effectiveness (Ke, nM) of naloxone and Mr 2266 in antagonizing a /x-ligand and two putative x-ligands 

Other /c-agonists are the tetrahydrofurfuryl derivative 49, the 3-methylfur-furyl derivative 50, and the open chain ether 51, all made by Boehringer Ingelheim/116 117 Structural features of /c-agonists based on the benzomor-phan skeleton, including conformational reasons for activity differences 

4-dichlorophenyl unit of U-50,488 also appears in the cyclohexane derivative 53 (p. 395), and in view of its morphinelike potencies in mouse WR and HP tests and failure to give Straub tails, there is a good case for its further examination as a putative x-agonist/119) 

Most recently certain benzodiazepines have been discovered that fail to bind to sites typical of the class but with selective actions on subpopulations of opioid receptor dependent upon their substituents. One agent, tifluadom (54) acts selectively on x-receptors as judged by the usual criteria/1201 Thus tifluadon displaced the x-ligand 3H(-)-bremazocine from GP brain and inhibited GPI contractions with IC50 values intermediate between those of ketazocine and bremazocine, and was also active in the rabbit VD preparation (believed rich in x-sites). It was three times as potent as morphine in mice by the TF test and its action was more readily blocked by Mr 2266 than naloxone. It did not depress respiration in rats and had a low PDC in monkeys. 

---