1 research outputs found
Novel Synthesis and Pharmacological Characterization of NOP Receptor Agonist 8-[(1<i>S</i>,3a<i>S</i>)-2,3,3a,4,5,6-Hexahydro-1<i>H</i>-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198)
The
nociceptin/orphanin FQ opioid peptide (NOP) receptor is a widely
expressed GPCR involved in the modulation of pain, anxiety, and motor
behaviors. Dissecting the functional properties of this receptor is
limited by the lack of systemically active ligands that are brain
permeant. The small molecule NOP receptor-selective, full agonist
8-[(1<i>S</i>,3a<i>S</i>)-2,3,3a,4,5,6-hexahydro-1<i>H</i>-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
(Ro 64-6198) hydrochloride is an active, brain penetrant ligand, but its difficult
and cost-prohibitive synthesis limits its widespread use and availability
for animal studies. Here, we detail a more efficient and convenient
method of synthesis, and use both in vitro and in vivo pharmacological
assays to fully characterize this ligand. Specifically, we characterize
the pharmacodynamics of Ro 64-6198 in cAMP and G-protein coupling
in vitro and examine, for the first time, the effects of nociceptin/orphanin
FQ and Ro 64-6198 in arrestin recruitment assays. Further, we examine
the effects of Ro 64-6198 on analgesia, anxiety, and locomotor responses
in vivo. This new synthesis and pharmacological characterization provide
additional insights into the useful, systemically active, NOP receptor
agonist Ro 64-6198