Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4‑(3-Hydroxy­phenyl)­piperidine Opioid Receptor Antagonists

In order to gain additional information concerning the active conformation of the <i>N</i>-substituted <i>trans</i>-3,4-dimethyl-4-(3-hydroxy­phenyl)­piperidine (<b>1</b>) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid <i>N</i>-substituted-6-(3-hydroxy­phenyl)­3-azabicyclo­[3.1.0]­hexane and 3-methyl-4-(3-hydroxy­phenyl)-4-azabicyclo­[4.1.0]­heptanes. Evaluation of the conformationally constrained series in a [³⁵S]­GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to <b>1</b>. The studies of the rigid compounds also suggested that the 3-methyl group present in compound <b>1</b> type antagonists may not be necessary for their pure opioid antagonist properties

Discovery of <i>N</i>‑{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)­piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [³⁵S]­GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold <b>21</b> was synthesized and tested for their ability to inhibit [³⁵S]­GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to <i>N</i>-[(1<i>S</i>)-1-{[(3<i>S</i>)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]­methyl}-2-methylpropyl]-4-phenoxybenzamide (<b>11a</b>), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on <b>11a</b> provided 28 novel analogues. Evaluation of these 28 compounds in the [³⁵S]­GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists