Design, Synthesis, and Pharmacological Evaluation of Nonsteroidal Tricyclic Ligands as Modulators of GABA Receptors.

GABA receptors (GABARs) are the major elements of inhibitory neurotransmission in the central nervous system (CNS). They are established targets for regulation by endogenous brain neuroactive steroids (NASs) such as pregnanolone. However, the complexity of de novo synthesis of NAS derivatives has hindered attempts to circumvent the principal limitations of using endogenous NASs, including selectivity and limited oral bioavailability.

CaMKIIα hub ligands are unable to reverse known phenotypes in Angelman syndrome mice.

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of ubiquitin-protein ligase E3A (UBE3A), resulting in marked changes in synaptic plasticity. In AS mice, a dysregulation of Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross-breeding experiments.

Exploring the NCS-382 Scaffold for CaMKIIα Modulation: Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKIIα Hub Domain.

Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a brain-relevant kinase and an emerging drug target for ischemic stroke and neurodegenerative disorders. Despite reported CaMKIIα inhibitors, their usefulness is limited by low subtype selectivity and brain permeability. ()-2-(5-Hydroxy-5,7,8,9-tetrahydro-6-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) is structurally related to the proposed neuromodulator, γ-hydroxybutyric acid, and is a brain-penetrating high nanomolar-affinity ligand selective for the CaMKIIα hub domain.

Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain.

The Ca/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac (). Herein, we employed approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with .

Tritium hydrogen-isotope exchange with electron-poor tertiary benzenesulfonamide moiety; application in late-stage labeling of T0901317.

The multifunctional radioligand [ H]T0901317 ([ H]1) has been employed as a powerful autoradiographic tool to target several receptors, such as liver X, farnesoid X, and retinoic acid-related orphan receptor alpha and gamma subtypes at nanomolar concentrations. Although [ H]1 is commercially available and its synthesis via tritiodebromination has been reported, the market price of this radioligand and the laborious synthesis of corresponding bromo-intermediate potentially preclude its widespread use in biochemical, pharmacological, and pathological studies in research lab settings. We exploit recent reports on hydrogen-isotope exchange (HIE) reactions in tertiary benzenesulfonamides where the sulfonamide represents an ortho-directing group that facilitates CH activation in the presence of homogenous iridium(I) catalysts.

Discovery of 2-(Imidazo[1,2- b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites.

Gabazine, a γ-aminobutyric acid type A (GABA) receptor antagonist, has previously been reported to inhibit the binding of [H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance γ-hydroxybutyric acid (GHB). We herein report a study on the structural determinants of gabazine for binding to (i) the orthosteric binding site of the GABA receptor and (ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2- b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogues with relatively high affinity ( K 0.

Molecular Hybridization of Potent and Selective γ-Hydroxybutyric Acid (GHB) Ligands: Design, Synthesis, Binding Studies, and Molecular Modeling of Novel 3-Hydroxycyclopent-1-enecarboxylic Acid (HOCPCA) and trans-γ-Hydroxycrotonic Acid (T-HCA) Analogs.

γ-Hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog trans-4-hydroxycrotonic acid (T-HCA).