ABSTRACT
Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, µ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
Subject(s)
Receptors, Opioid/agonists , Small Molecule Libraries/chemistry , Spiro Compounds/chemistry , Animals , Anxiety/drug therapy , Disease Models, Animal , Motor Activity/drug effects , Opioid Peptides/chemistry , Opioid Peptides/metabolism , Protein Binding , Rats , Receptors, Opioid/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Structure-Activity Relationship , Nociceptin Receptor , NociceptinABSTRACT
Transgenic mouse models of Alzheimer's disease (AD) are being utilized as models for elucidating AD etiology and potential therapeutic approaches. However, two major drawbacks of these models are: (1) transgenic animals often over-express amyloid beta (Abeta) to high levels compared to that seen in sporadic human AD and (2) the current intellectual property issues surrounding a number of these models make them difficult to utilize in a commercial setting. Our goal was to identify an appropriate non-transgenic mouse strain, devoid of these patent restrictions and test whether amyloid-modulating compounds will lower total brain and plasma Abeta. Plasma and brain samples were collected from eight commonly used mouse strains (C57BL/6, SJL, CF-1, DBA/2, CD-1, 129, FVB and B6D2F1; Charles River Labs) and total Abetalevels were validated and quantified with a rodent-specific monoclonal Abetaantibody. Plasma Abeta in SJL mice was the highest of the eight strains tested (213 pM +/- 21 pM), but was not significantly different than the seven other strains. Total brain Abeta in SJL mice was also the greatest of the mouse strains tested (356 pM +/- 73 pM). SJL, C57BL/6 and CF-1 mice had total brain Abeta levels that were significantly greater than Abeta levels in B6D2F1 mice (242 +/- 20 pM). In vivo efficacy of an Abeta lowering agent was observed in CF-1 mice upon oral administration of the gamma-secretase inhibitors, DAPT and LY-411575. The absolute levels of rodent brain Abeta detected and the efficacy of the gamma-secretase treatment were dependent upon the antibodies used, as well as the extraction methodology. The measurement of total brain Abeta lowering in a common mouse strain could help accelerate drug discovery programs for Alzheimer's disease without relying on costly transgenic animals that overexpress APP in a manner that may not be predictive of the effects of these compounds in human AD.
