The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist

The clinical efficacy of opioid receptor antagonists for the treatment of opioid-induced constipation (OIC) is established. Peripherally selective antagonists are intended to provide OIC symptom relief without compromising the analgesic effects of centrally penetrant opioid agonists. We describe the in vitro profile of a novel opioid receptor antagonist, TD-1211, at recombinant (human μ and δ, and guinea pig κ) and rodent native opioid receptors. TD-1211 bound with high affinity to human recombinant μ and δ, and guinea pig κ receptors expressed in CHO-K1 cells (pK _d?=?9.7, 8.6, and 9.9, respectively). The in vitro receptor selectivity of TD-1211 (μ?≈?κ?>?δ) is similar to that for the peripherally-selective opioid receptor antagonist methylnaltrexone, but contrasts with the μ selectivity of alvimopan. Functionally, TD-1211 behaved as an antagonist at all three receptor types in both recombinant expression systems (pK _b?=?9.6, 8.8 and 9.5, at μ, δ, and κ, respectively) and rodent native tissue preparations (μ and κ pA₂s?=?10.1 and 8.8, respectively (guinea pig ileum), and δ pK _b?=?8.4 (hamster vas deferens)). TD-1211 displayed a high degree of selectivity for opioid receptors over a broad panel of cellular targets. These in vitro data justified investigation of the preclinical in vivo activity of TD-1211 (Armstrong et al., Naunyn-Schmiedeberg’s Arch Pharm, 2013).