Ki: 0.02 nM (δ opioid), 64 nM (μ opioid), 66 nM (κ opioid)

Opioid drugs exert a wide spectrum of physiological and behavioral effects. These effects are mediated via membrane-bound receptors, of which the best characterized are the kappa, delta, and mu receptors. Naltrindole inhibits the proliferation of cultured human U266 MM cells in a time- and dose-dependent manner with an EC ₅₀ of 16 μM. Treatment of U266 cells with naltrindole significantly decreases the level of the active, phosphorylated form of the kinases, extracellular signal-regulated kinase and Akt, which may be related to its antiproliferative activity. Naltrindole inhibits growth and induces apoptosis in the three characteristic SCLC cell lines, NCI-H69, NCI-H345, and NCI-H510. Naltrindole treatment reduces constitutive phosphorylation of Akt/PKB on serine 473 and threonine 308 in cells and also its downstream effectors glycogen synthase kinase-3β and the Forkhead transcription factors AFX and FKHR.

Naltrindole significantly decreases tumor cell volumes in human MM cell xenografts in severe combined immunodeficient mice. In mice, naltrindole at 20 mg/kg s.c. antagonizes the δ-selective agonist effect of [D- Ser, Leu, Thr]enkephalin (DSLET) without blocking the antinociceptive effect of morphine or U50488H. Naltrindole is the only highly selective δ antagonist that is active upon peripheral administration. Acute naltrindole induces significant decreases in external and total ambulation (horizontal activity) and rearing behaviour (vertical activity), as well as a significant increase in grooming frequency. In animals chronically treated with naltrindole there is an increase in total ambulation one day after the discontinuation of the treatment.