Synthesis and pharmacological evaluation of an 8/3-bis(2-chloroethyl)amino opiate as a nonequilibrium opioid receptor probe

8β-[Bis(2-chloroethyl)amino]-6,7-didehydro-3-hydroxy-17-methyl-4, 5α-epoxymorphinan (3) was synthesized from codeine, and its configuration at C-8 was determined by NMR. When evaluated in the guinea pig ileum and mouse vas deferens preparations, 3 was found to be a feeble, reversible agonist in both tissues without any irreversible agonist or antagonist activity. The fact that the 8β-bis-(2-hydroxyethyl)amino analogue was devoid of opioid activity suggests that steric hindrance to ligand-receptor association by a bulky 8-substituent may be responsible for this inactivity.