Occupancy of Nociceptin/Orphanin FQ Peptide Receptors by the Antagonist LY2940094 in Rats and Healthy Human Subjects.

Therapeutic benefits from nociceptin opioid peptide receptor (NOP) antagonism were proposed for obesity, eating disorders, and depression. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) is a novel, orally bioavailable, potent, and selective NOP antagonist. We studied NOP receptor occupancy (RO) after single oral LY2940094 doses in rat hypothalamus and human brain by use of liquid chromatography with tandem mass spectrometry (LC-MS/MS) (LSN2810397) and positron emission tomography (PET) ([(11)C]NOP-1A) tracers, respectively. A bolus plus constant infusion tracer protocol with PET was employed in humans at 2.5 and 26.5 hours after administration of the LY2940094 dose. The RO was calculated from the change in regional distributional volume (VT) corrected for nondisplaceable volume using Lasson plots. The RO followed a simple Emax relationship to plasma LY2940094 concentration, reaching near complete occupancy in both species. For rat hypothalamus, the plasma concentration at half-maximum RO (EC50) was 5.8 ng/ml. In humans, LY2940094 was well tolerated and safe over the 4-40 mg dose range, and it peaked in plasma at 2 to 6 hours after a 1- to 2-hour lag, with approximate dose-proportional exposure. After 4-40 mg doses, NOP RO was similar across the prefrontal cortex, occipital cortex, putamen, and thalamus, with EC50 of 2.94 to 3.46 ng/ml, less than 2-fold lower than in rats. Over 4-40 mg doses, LY2940094 mean plasma levels at peak and 24 hours were 7.93-102 and 1.17-14.1 ng/ml, corresponding to the cross-region average NOP RO of 73%-97% and 28%-82%, respectively. The rat EC50 translates well to humans. LY2940094 readily penetrates the human brain, and a once-daily oral dose of 40 mg achieves sustainably high (>80%) NOP RO levels suitable for testing clinical efficacy.

Safety, tolerability, pharmacokinetics, and effects on human experimental pain of the selective ionotropic glutamate receptor 5 (iGluR5) antagonist LY545694 in healthy volunteers.

The objective of this study was to establish in healthy volunteers the maximally tolerated multiple dose (MTMD) of the ionotropic glutamate receptor 5 antagonist LY545694 (part A), and to investigate whether that dose had analgesic or antihyperalgesic effects in the brief thermal stimulation (BTS) pain model (Part B). Part A was a double-blind, placebo-controlled study in 3 groups of 10 healthy men. To simulate an extended-release formulation, study drug was administered orally over 6hours (12 equally divided aliquots at 30-minute intervals). Part B was a double-blind, placebo-controlled, double-dummy, 3-way crossover study in 27 healthy men. At each of the 3 study periods, subjects received either LY545694 (MTMD; as determined during part A) as a simulated, twice daily extended-release formulation for 4 doses over 3days, gabapentin (600mg 8hours apart; 6 doses over 3days; positive control), or matching placebo. The BTS model was induced twice with a 1-hour interval on each of the 2 study days, before drug administration and at the time of expected peak analgesia of LY545694. Plasma exposure for LY545694 was approximately linear over the 25- to 75-mg dose range. The MTMD of LY545694 was 25mg twice daily. Areas of secondary hyperalgesia were significantly smaller after administration of LY545694 and gabapentin compared with placebo (P<.0001 and P=.0004, respectively), but there was no difference between areas after administration of gabapentin and LY545694 (P=.400). Neither gabapentin nor LY545694 reduced the painfulness of skin heating during BTS model induction. The most common treatment-emergent adverse event was dizziness. The results of this study suggest that LY545694 should be explored further as a potential treatment for chronic pain involving neuronal sensitization.