Are Pure Opioid Receptor Antagonists

ABSTRACT This report describes the discovery that 1-substituted 4-(3-hydroxy-phenyl)piperazines are pure opioid receptor antagonists. Compounds in this new series include N-phenylpropyl (3S)-3-methyl-4-(3-hydroxyphenyl)piperazine and (3R)-3-methyl-4-(3-hydroxyphenyl)piperazine, both of which display low nano-molar potencies at μ, δ, and κ receptors and pure antagonist properties in a [35S]GTPγS assay. KEYWORDS Opioid antagonists, 4-(3-hydroxyphenyl)piperazines The opioid receptors, μ, δ, and κ, and the opioid-likereceptor ORL-1 belong to the superfamily of G-proteincoupled receptors (GPCRs) that possess seven helical trans-membrane spanning domains in their architecture.1 These opioid receptors have been extensively studied, and thousands of compounds have been synthesized and eval-uated by in vitro binding and functional assays as well as by animal models.2 An integral part of the effort to characterize the opioid receptor system has been the discovery of potent, pure antagonists. Naloxone (1a) and naltrexone (1b), bot