DPI-3290 [(+)-3-((α-R)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A Mixed Opioid Agonist with Potent Antinociceptive Activity

Abstract

Compound (+)-3-((α-R)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), is one of a series of novel centrally acting agents with potent antinociceptive activity that binds specifically and with high affinity to opioid receptors. In saturation equilibrium binding studies performed at 25°C using membranes from rat brain or guinea pig cerebellum, the K_i values measured for DPI-3290 at δ-, μ-, and κ-opioid receptors were 0.18 ± 0.02, 0.46 ± 0.05, and 0.62 ± 0.09 nM, respectively. In vas deferens isolated from laboratory mice, DPI-3290 decreased electrically induced tension development in a concentration-dependent manner with corresponding IC₅₀ values of 1.0 ± 0.3, 6.2 ± 2.0, and 25.0 ± 3.3 nM at δ-, μ-, and κ-receptors, respectively. The activity of DPI-3290 in isolated vas deferens tissue was approximately 20,000, 175.8, and 1500 times more efficacious than morphine, and 492, 2.5, and 35 times more efficacious than fentanyl at δ-, μ-, and κ-receptors, respectively. In ileal strips isolated from guinea pigs, DPI-3290 inhibited tension development with a corresponding IC₅₀ value of 3.4 ± 1.6 nM at μ-opioid receptors and 6.7 ± 1.6 nM at κ-opioid receptors. Intravenous administration of 0.05 ± 0.007 mg/kg DPI-3290 produced a 50% antinociceptive response in rats. The antinociceptive properties of DPI-3290 were blocked by naloxone (0.5 mg/kg s.c.). Compared with morphine, this study demonstrated that DPI-3290 is more potent and elicited a similar magnitude of antinociceptive activity in the rat, actions mediated by its mixed opioid receptor agonist activity. The marked antinociceptive activity of DPI-3290 will likely provide a means for relieving severe pain in patients that require analgesic treatment.