Salvinorin A, an Active Component of the Hallucinogenic Sage Salvia divinorum Is a Highly Efficacious κ-Opioid Receptor Agonist: Structural and Functional Considerations

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Abstract
The in vitro pharmacological properties of N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]-acrylamide (JNJ-5207787), a novel neuropeptide Y Y2 receptor (Y2) antagonist, were evaluated. JNJ-5207787 inhibited the binding of peptide YY (PYY) to human Y2 receptor in KAN-Ts cells (pIC50 = 7.00 ± 0.10) and to rat Y2 receptors in rat hippocampus (pIC50 = 7.10 ± 0.20). The compound was >100-fold selective versus human Y1,Y4, and Y5 receptors as evaluated by radioligand binding. In vitro receptor autoradiography data in rat brain tissue sections confirmed the selectivity of JNJ-5207787. [125I]PYY binding sites sensitive to JNJ-5207787 were found in rat brain regions known to express Y2 receptor (septum, hypothalamus, hippocampus, substantia nigra, and cerebellum), whereas insensitive binding sites were observed in regions known to express Y1 receptor (cortex and thalamus). JNJ-5207787 was demonstrated to be an antagonist via inhibition of PYY-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate binding ([35S]GTPγS) in KAN-Ts cells (pIC50 corrected = 7.20 ± 0.12). This was confirmed auto-radiographically in rat brain sections where PYY-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate binding was inhibited by JNJ-5207787 (10 μM) in hypothalamus, hippocampus, and substantia nigra. After intraperitoneal administration in rats (30 mg/kg), JNJ-5207787 penetrated into the brain (Cmax = 1351 ± 153 ng/ml at 30 min) and occupied Y2 receptor binding sites as revealed by ex vivo receptor autoradiography. Hence, JNJ-5207787 is a potent and selective pharmacological tool available to establish the potential role of central and peripheral Y2 receptors in vivo.