N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: A novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues

The design, synthesis, and pharmacological evaluation of a novel class of d elta opioid receptor agonists, N,N-diethyl-4-(phenylpiperidin-4-ylidenemeth yl)benzamide (6a) and its analogues, are described. These compounds, formal ly derived from SNC-80 (2) by replacing the piperazine ring with a piperidi ne ring containing an exocyclic carbon carbon double bond, were found to bi nd with high affinity and exhibit excellent selectivity for thee opioid rec eptor as full agonists. 6a, the simplest structure in the class, exhibited an IC50 = 0.87 nM for the delta opioid receptors and extremely high selecti vity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa /delta = 8590). Rat liver microsome studies on a selected number of compoun ds show these olefinic piperidine compounds (6) to be considerably more sta ble than SNC-80. This novel series of compounds appear to interact with del ta opioid receptors in a similar way to SNC-80 since they demonstrate simil ar SAR. Two general approaches have been established for the synthesis of t hese compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.