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
A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Models, Molecular , Quinazolines/chemical synthesis , Amyloid Precursor Protein Secretases/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Aspartic Acid Endopeptidases/chemistry , CHO Cells , Caco-2 Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Crystallography, X-Ray , Humans , Hydrogen Bonding , Molecular Conformation , Mutation , Oligopeptides/chemistry , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/blood , Peptide Fragments/metabolism , Quinazolines/chemistry , Quinazolines/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Expression of the neuropeptide galanin is markedly upregulated within the adult dorsal root ganglion (DRG) after peripheral nerve injury. We demonstrated previously that the rate of peripheral nerve regeneration is reduced in galanin knock-out mice, with similar deficits observed in neurite outgrowth from cultured mutant DRG neurons. Here, we show that the addition of galanin peptide significantly enhanced neurite outgrowth from wild-type sensory neurons and fully rescued the observed deficits in mutant cultures. Furthermore, neurite outgrowth in wild-type cultures was reduced to levels observed in the mutants by the addition of the galanin antagonist M35 [galanin(1-13)bradykinin(2-9)]. Study of the first galanin receptor (GalR1) knock-out animals demonstrated no differences in neurite outgrowth compared with wild-type animals. Similarly, use of a GalR1-specific antagonist had no effect on neuritogenesis. In contrast, use of a GalR2-specific agonist had equipotent effects on neuritogenesis to galanin peptide, and inhibition of PKC reduced neurite outgrowth from wild-type sensory neurons to that observed in galanin knock-out cultures. These results demonstrate that adult sensory neurons are dependent, in part, on galanin for neurite extension and that this crucial physiological process is mediated by activation of the GalR2 receptor in a PKC-dependent manner.
Subject(s)
Bradykinin/analogs & derivatives , Neurites/metabolism , Neurons, Afferent/metabolism , Receptors, Neuropeptide/metabolism , Animals , Bradykinin/pharmacology , Cells, Cultured , Female , Galanin/antagonists & inhibitors , Galanin/genetics , Galanin/pharmacology , Ganglia, Spinal/cytology , Homozygote , Mice , Mice, Knockout , Mice, Mutant Strains , Nerve Regeneration/physiology , Neurites/drug effects , Neurons, Afferent/cytology , Neurons, Afferent/drug effects , Peptide Fragments/pharmacology , Protein Kinase C/metabolism , Receptors, Galanin , Receptors, Neuropeptide/antagonists & inhibitors , Receptors, Neuropeptide/geneticsABSTRACT
The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on (125)I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC(50). When delivered intraperitoneally, compounds 3a, 3b, and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.
Subject(s)
Feeding Behavior/drug effects , Receptors, Corticotropin/agonists , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , alpha-MSH/analogs & derivatives , Animals , Disease Models, Animal , Fasting/physiology , Feeding Behavior/physiology , Humans , Infusions, Parenteral , Inhibitory Concentration 50 , Iodine Radioisotopes , Male , Melanoma/metabolism , Rats , Rats, Long-Evans , Receptor, Melanocortin, Type 4 , Receptors, Corticotropin/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured , alpha-MSH/metabolismABSTRACT
A concise synthesis of the beta-amyloid(1-42 )aggregation inhibitor (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(-)-2] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene into amine. Enantiomeric resolution was achieved by recrystallization of amine as the dibenzoyl-D-tartaric acid salt. Hydroquinone is a potent inhibitor of the fibrillar aggregation of beta-amyloid as determined in two different assay systems.
