N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide:  A Novel, Exceptionally Selective, Potent δ Opioid Receptor Agonist with Oral Bioavailability and Its Analogues

The design, synthesis, and pharmacological evaluation of a novel class of δ opioid receptor agonists, N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (<BO>6a</BO>) and its analogues, are described. These compounds, formally derived from SNC-80 (<BO>2</BO>) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the δ opioid receptor as full agonists. <BO>6a</BO>, the simplest structure in the class, exhibited an IC<INF>50</INF> = 0.87 nM for the δ opioid receptors and extremely high selectivity over the μ receptors (μ/δ = 4370) and the κ receptors (κ/δ = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (<BO>6</BO>) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with δ opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (<BO>7</BO>) and Suzuki coupling reactions of vinyl bromide (<BO>8</BO>), and are herewith reported.