Abstract

In the present article, we summarize the preclinical pharmacology of 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327), a highly potent and selective agonist of the δ-opioid receptor. AZD2327 binds with sub-nanomolar affinity to the human opioid receptor (K_i = 0.49 and 0.75 nM at the C27 and F27 isoforms, respectively) and is highly selective (>1000-fold) over the human μ- and κ-opioid receptor subtypes as well as >130 other receptors and channels. In functional assays, AZD2327 shows full agonism at human δ-opioid receptors ([³⁵S]GTPγ EC₅₀ = 24 and 9.2 nM at C27 and F27 isoforms, respectively) and also at the rat and mouse δ-opioid receptors. AZD2327 is active in a wide range of models predictive of anxiolytic activity, including a modified Geller-Seifter conflict test and social interaction test, as well as in antidepressant models, including learned helplessness. In animals implanted with microdialysis probes and then given an acute stressor by pairing electric shock delivery with a flashing light, there is an increase in norepinephrine release into the prefrontal cortex associated with this acute anxiety state. Both the benzodiazepine anxiolytic standard diazepam and AZD2327 blocked this norepinephrine release equally well, and there was no evidence of tolerance to these effects of AZD2327. Overall, these data support the role of the δ-opioid receptor in the regulation of mood, and data suggest that AZD2327 may possess unique antidepressant and anxiolytic activities that could make a novel contribution to the pharmacotherapy of psychiatric disorders.