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

Abstract

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.

Preclinical findings predicting efficacy and side‐effect profile of LY 2940094, an antagonist of nociceptin receptors

“…) and human brain (Raddad et al. ) appear to be required for efficacy in preclinical models (current report) and in patients (Post et al. ).…”

“…The preclinical findings reported here provided the opportunity to determine the necessary and sufficient biological outputs in rodents that predicted the translation to efficacy in MDD patients. In the case of LY2940094, high NOP receptor occupancy in both rodent (Toledo et al 2014) and human brain (Raddad et al 2016) appear to be required for efficacy in preclinical models (current report) and in patients (Post et al 2016). The high levels of monoamines detected in rodent prefrontal cortex in response to conventional antidepressants (e.g., Jordan et al 1994) are clearly not required for predicting patient efficacy (Post et al 2016).…”

“…; compound 36; Statnick et al. ), which translates to the ability to sufficiently occupy NOP receptors in the brain as measured with PET imaging (Raddad et al., ). LY2940094 has nM potency for binding and functional activity at human and rat NOP receptors with over a 4000× separation in affinity for mu, kappa, or delta opioid receptors (Toledo et al.…”

“…The NOP receptor antagonist LY2940094 was an ideal tool to test the translational hypothesis that NOP receptor blockade would be antidepressant in MDD patients. The molecule demonstrates high potency and selectivity for NOP receptors along with good oral bioavailability (Toledo et al 2014;compound 36;Statnick et al 2016), which translates to the ability to sufficiently occupy NOP receptors in the brain as measured with PET imaging (Raddad et al, 2016). LY2940094 has nM potency for binding and functional activity at human and rat NOP receptors with over a 40009 separation in affinity for mu, kappa, or delta opioid receptors (Toledo et al 2014;Statnick et al 2016).…”

Proof‐of‐Concept Study to Assess the Nociceptin Receptor Antagonist LY2940094 as a New Treatment for Alcohol Dependence

“…The dose selected was based on pharmacokinetic and positron emission tomography data from healthy subjects. LY2940094 40 mg was predicted to maintain NOP receptor occupancy above 70% throughout the dosing interval upon once‐daily oral dosing (Raddad et al, ). Additionally, this dose had previously been demonstrated as being safe and well tolerated in clinical pharmacology studies in healthy subjects for up to 14 days as well as in a study of major depressive disorder patients (Post et al., ).…”