2 research outputs found
Caged Naloxone: Synthesis, Characterization, and Stability of 3â<i>O</i>â(4,5-Dimethoxy-2-nitrophenyl)carboxymethyl Naloxone (CNV-NLX)
The
photolabile analogue of the broad-spectrum opioid antagonist
naloxone, 3-<i>O</i>-(4,5-dimethoxy-2-nitrophenyl)Âcarboxymethyl
naloxone (also referred to as âcaged naloxoneâ, 3-<i>O</i>-(α-carboxy-6-nitroveratryl)Ânaloxone, CNV-NLX), has
been found to be a valuable biochemical probe. While the synthesis
of CNV-NLX is simple, its characterization is complicated by the fact
that it is produced as a mixture of α<i>R</i>,5<i>R</i>,9<i>R</i>,13<i>S</i>,14<i>S</i> and α<i>S</i>,5<i>R</i>,9<i>R</i>,13<i>S</i>,14<i>S</i> diastereomers. Using long-range
and heteronuclear NMR correlations, the <sup>1</sup>H NMR and <sup>13</sup>C NMR resonances of both diastereomers have been fully assigned,
confirming the structures. Monitoring of solutions of CNV-NLX in saline
buffer, in methanol, and in DMSO has shown CNV-NLX to be stable for
over a week under fluorescent laboratory lights at room temperature.
Exposure of such solutions to λ 365 nm from a hand-held UV lamp
led to the formation of naloxone and CNV-related breakdown products
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