Discovery and Pharmacological Evaluation of a Diphenethylamine Derivative (HS665), a Highly Potent and Selective κ Opioid Receptor Agonist

Abstract

Here we report on the design, synthesis, and biological characterization of novel κ opioid (KOP) receptor ligands of diphenethylamines. In opioid receptor binding and functional assays, the N-cyclobutylmethyl substituted derivative 4 (HS665) showed the highest affinity and selectivity for the KOP receptor and KOP agonist potency. Compound 4 inhibited acetic acid induced writhing after subcutaneous administration in mice via KOP receptor-mediated mechanisms, being equipotent as an analgesic to the KOP agonist U50,488.

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

“…Several KOR-selective pharmacophores have been recently reported and characterized (Frankowski et al, 2010, 2012; Nagase et al, 2010; Spetea et al, 2012; Bourgeois et al, 2014; Hirayama et al, 2014; Riley et al, 2014; Scarry et al, 2016). The current study follows from a report (Spetea et al, 2012) of novel compounds based on a diphenethylamine structural backbone known to interact with the dopamine D2 receptor and reported to also have KOR antagonist activity in in vitro rodent tissue binding assays and bioassays (Fortin et al, 1991).…”

“…The current study follows from a report (Spetea et al, 2012) of novel compounds based on a diphenethylamine structural backbone known to interact with the dopamine D2 receptor and reported to also have KOR antagonist activity in in vitro rodent tissue binding assays and bioassays (Fortin et al, 1991). The novel compounds in this series were studied in KOR radioligand binding and [ 35 S]GTPγS binding stimulation in vitro, with the same assays performed with membranes prepared from cell lines expressing MOR or DOR, as well as dopamine D1, D2, or D3 receptors (Spetea et al, 2012). The compound that had the highest affinity for KOR was N -methylcyclobutyl- N -phenylethyl- N -3-hydroxyphenylethyl-amine (Figure 1A, MCBPHA, referred to as HS-665, compound 4 in Spetea et al, 2012).…”

“…The novel compounds in this series were studied in KOR radioligand binding and [ 35 S]GTPγS binding stimulation in vitro, with the same assays performed with membranes prepared from cell lines expressing MOR or DOR, as well as dopamine D1, D2, or D3 receptors (Spetea et al, 2012). The compound that had the highest affinity for KOR was N -methylcyclobutyl- N -phenylethyl- N -3-hydroxyphenylethyl-amine (Figure 1A, MCBPHA, referred to as HS-665, compound 4 in Spetea et al, 2012). MCBHPA was reported to have 90% intrinsic activity in KOR [ 35 S]GTPγS assays, with low affinity and no agonism at the dopamine D2 receptor.…”

“…This compound was further characterized in an in vivo acetic acid writhing analgesia assay in mice. It was demonstrated to be equally potent as the well-characterized KOR agonist U50,488 in peripheral analgesia, and the effect was blocked by a KOR antagonist (Spetea et al, 2012). In an additional recent study, MCBPHA, as well as a structurally related methylcyclopropyl derivative, was further characterized in vitro and in vivo (Spetea et al, 2017).…”

“…Of the other remaining compounds reported in the 2012 study, one, N -butyl- N -phenylethyl- N -3-hydroxyphenylethyl-amine (BPHA; Figure 1B), was found to exhibit high affinity at KOR in radioligand binding, no appreciable activity at the dopamine receptors, and partial [ 35 S]GTPγS agonist activity (45.5% intrinsic activity in KOR [ 35 S]GTPγS assay). Further, this compound was found to exhibit approximate 40-fold selectivity for KOR compared with MOR (and over 200-fold selectivity for KOR vs DOR) (Spetea et al, 2012). …”