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 mu and delta, and guinea pig kappa) and rodent native opioid receptors. TD-1211 bound with high affinity to human recombinant mu and delta, and guinea pig kappa receptors expressed in CHO-K1 cells (pK (d) = 9.7, 8.6, and 9.9, respectively). The in vitro receptor selectivity of TD-1211 (mu a parts per thousand aEuro parts per thousand I(0)aEuro parts per thousand > I ') is similar to that for the peripherally-selective opioid receptor antagonist methylnaltrexone, but contrasts with the mu 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 mu, delta, and kappa, respectively) and rodent native tissue preparations (mu and kappa pA(2)s = 10.1 and 8.8, respectively (guinea pig ileum), and delta 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).