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We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.

The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) 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 delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta 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 (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.