Concepcion Pedregal

LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders

Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (t(max): 1-2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED₅₀ = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders.

Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures.

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

Brain and Whole-Body Imaging in Rhesus Monkeys of 11C-NOP-1A, a Promising PET Radioligand for Nociceptin/Orphanin FQ Peptide Receptors

Our laboratory developed (S)-3-(2′-fluoro-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-c]pyran]-1-yl)-2-(2-fluorobenzyl)-N-methylpropanamide (11C-NOP-1A), a new radioligand for the nociceptin/orphanin FQ peptide (NOP) receptor, with high affinity (Ki, 0.15 nM) and appropriate lipophilicity (measured logD, 3.4) for PET brain imaging. Here, we assessed the utility of 11C-NOP-1A for quantifying NOP receptors in the monkey brain and estimated the radiation safety profile of this radioligand based on its biodistribution in monkeys. Methods: Baseline and blocking PET scans were acquired from head to thigh for 3 rhesus monkeys for approximately 120 min after 11C-NOP-1A injection. These 6 PET scans were used to quantify NOP receptors in the brain and to estimate radiation exposure to organs of the body. In the blocked scans, a selective nonradioactive NOP receptor antagonist (SB-612111; 1 mg/kg intravenously) was administered before 11C-NOP-1A. In all scans, arterial blood was sampled to measure the parent radioligand 11C-NOP-1A. Distribution volume (VT; a measure of receptor density) was calculated with a compartment model using brain and arterial plasma data. Radiation-absorbed doses were calculated using the MIRD Committee scheme. Results: After 11C-NOP-1A injection, peak uptake of radioactivity in the brain had a high concentration (∼5 standardized uptake value), occurred early (∼12 min), and thereafter washed out quickly. VT (mL · cm−3) was highest in the neocortex (∼20) and lowest in hypothalamus and cerebellum (∼13). SB-612111 blocked approximately 50%–70% of uptake and reduced VT in all brain regions to approximately 7 mL · cm−3. Distribution was well identified within 60 min of injection and stable for the remaining 60 min, consistent with only parent radioligand and not radiometabolites entering the brain. Whole-body scans confirmed that the brain had specific (i.e., displaceable) binding but could not detect specific binding in peripheral organs. The effective dose for humans estimated from the baseline scans in monkeys was 5.0 μSv/MBq. Conclusion: 11C-NOP-1A is a useful radioligand for quantifying NOP receptors in the monkey brain, and its radiation dose is similar to that of other 11C-labeled ligands for neuroreceptors. 11C-NOP-1A appears to be a promising candidate for measuring NOP receptors in the human brain.