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.
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Bivalent ligands, compounds that contain two recognition sites joined through a connecting spacer, have attracted considerable interest as molecular probes because some of them display considerable selectivity for a single opioid receptor type. For example, the triethylenedioxy derivative of fl-naltrexamine (TENA) (Portoghese and Takemori, 1985), binaltorphimine (BNI) and nor-BNI (Portoghese et al., 1987) are bivalent ligands selective for K opioid receptors. Previously, a series of bivalent ligands with fl-naltrexamine as the 1 This investigation was supported by USPHS grants from the National Institute on Drug Abuse. Studies in this report were carried out in accordance with the Declaration of Helsinki and/or with the guide for the care and use of laboratory animals as adopted and promulgated by the Na-tional Institutes of Health. Correspondence to: A.E. Takemori, Department of Pharmacology, 3-249 Millard Hall, University of Minnesota, 435 Delaware St. S.E., Minneapolis, MN 55455 U.S.A.
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- (Long acting)
- Naltrexamine bivalent ligands
- μ-Opioid receptor antagonists