Effects of polar κ receptor agonists designed for the periphery on ATP-induced Ca 2+ release from keratinocytes

In order to obtain polar κ agonists, which cannot pass the blood–brain barrier, secondary amines 3a and 3b were reductively alkylated with pyridine-3-carbaldehyde to give pyridylmethyl substituted perhydroquinoxalines 5a and 5b , respectively. Both 5a and 5b show very high κ-opioid receptor affinity with K i values of 0.13 nM and 3.8 nM, respectively. Moreover, they are very selective for the κ receptor. In the [ 35 S]GTPγS assay, both quinoxalines reached full agonistic activity. With an EC 50 value of 34 nM, 5a is only slightly less potent than the prototypical κ agonist U-69,593. For the determination of the log D values, a shake-flask method was developed, making use of quantification by mass spectrometry which requires only very small amounts of the compound (