2 research outputs found
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 [<sup>35</sup>S]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 [<sup>35</sup>S]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
[<sup>35</sup>S]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 [<sup>35</sup>S]GTPγS binding assay showed that several of the analogues
were potent and selective κ opioid receptor antagonists