Analgetic activity and in vitro binding constants of some N-alkyl-3-benzazocines

A homologous series of 3-alkyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazocines (2) has been synthesized. Analgetic activity and binding constants for the opiate receptor for 2 and for an analogous series of benzomorphans (1 and 3) are reported. In 1, hot-plate analgesic activity is lost on increase of the N-alkyl chain length from ethyl through butyl (lc-e) and regained with amyl (lf) and hexyl (lg). Compounds lc-e show that antagonist properties and binding constants are similar throughout the series. With 2, where there has been loss of steric constraints through removal of the 2,6-methano bridge of 1 and 3, greatly diminished analgetic activity and receptor affinity and no antagonist properties were observed. Like 1, however, greatest agonist activity was shown by the N-methyl (2c), amyl (2g), hexyl (2h), and heptyl (2i) homologs and there is a parallel of in vitro binding strength and analgetic activity.