Long-acting agonist and antagonist activities of naltrexamine bivalent ligands in mice

A series of naltrexamine bivalent ligands, compounds with two naltrexamine pharmacophores separated by a spacer which contains a variable number of glycyl units flanking a succinyl group, were synthesized and evaluated in vivo in mice. These compounds possessed long-acting agonist and especially antagonist activities. The bivalent ligands, 2 and 3 displayed antinociceptive activity that lasted > 4h. Compound 1, a bivalent ligand and 4, the monomer, antagonized the antinociceptive effect of morphine for a week after a single injection i.c.v. The long duration of action may be due to entrapment of these ligands in the central nervous system. These compounds may give future insights into the design of long-acting agonists and antagonists.