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Perspective: Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors.

ABSTRACT: The concept of ligand-receptor binding kinetics has been broadly applied in drug development pipelines focusing on G protein-coupled receptors (GPCRs). The ligand residence time (RT) for a receptor describes how long a ligand-receptor complex exists, and is defined as the reciprocal of the dissociation rate constant (k _off). RT has turned out to be a valuable parameter for GPCR researchers focusing on drug development as a good predictor of in vivo efficacy. The positive correlation between RT and in vivo efficacy has been established for several drugs targeting class A GPCRs (e.g., the neurokinin-1 receptor (NK₁R), the β₂ adrenergic receptor (β₂AR), and the muscarinic 3 receptor (M₃R)) and for drugs targeting class B1 (e.g., the glucagon-like peptide 1 receptor (GLP-1R)). Recently, the association rate constant (k _on) has gained similar attention as another parameter affecting in vivo efficacy. In the current perspective, we address the importance of studying ligand-receptor binding kinetics for therapeutic targeting of GPCRs, with an emphasis on how binding kinetics can be altered by subtle molecular changes in the ligands and/or the receptors and how such changes affect treatment outcome. Moreover, we speculate on the impact of binding kinetic parameters for functional selectivity and sustained receptor signaling from endosomal compartments; phenomena that have gained increasing interest in attempts to improve therapeutic targeting of GPCRs.

SUBMITTER: van der Velden WJC

PROVIDER: S-EPMC7155193 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Perspective: Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors.

van der Velden Wijnand J C WJC Heitman Laura H LH Rosenkilde Mette M MM

ACS pharmacology & translational science 20200318 2

The concept of ligand-receptor binding kinetics has been broadly applied in drug development pipelines focusing on G protein-coupled receptors (GPCRs). The ligand residence time (RT) for a receptor describes how long a ligand-receptor complex exists, and is defined as the reciprocal of the dissociation rate constant (k off). RT has turned out to be a valuable parameter for GPCR researchers focusing on drug development as a good predictor of in vivo efficacy. The positive ...[more]

PMID: 32296761

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Project description:Alzheimer's disease (AD), particularly its sporadic or late-onset form (SAD/LOAD), is the most prevalent (96-98% of cases) neurodegenerative dementia in aged people. AD's neuropathology hallmarks are intrabrain accumulation of amyloid-? peptides (A?s) and of hyperphosphorylated Tau (p-Tau) proteins, diffuse neuroinflammation, and progressive death of neurons and oligodendrocytes. Mounting evidences suggest that family C G-protein-coupled receptors (GPCRs), which include ?-aminobutyric acid B receptors (GABABRs), metabotropic glutamate receptors (mGluR1-8), and the calcium-sensing receptor (CaSR), are involved in many neurotransmitter systems that dysfunction in AD. This review updates the available knowledge about the roles of GPCRs, particularly but not exclusively those expressed by brain astrocytes, in SAD/LOAD onset and progression, taking stock of their respective mechanisms of action and of their potential as anti-AD therapeutic targets. In particular, GABABRs prevent A?s synthesis and neuronal hyperexcitability and group I mGluRs play important pathogenetic roles in transgenic AD-model animals. Moreover, the specific binding of A?s to the CaSRs of human cortical astrocytes and neurons cultured in vitro engenders a pathological signaling that crucially promotes the surplus synthesis and release of A?s and hyperphosphorylated Tau proteins, and also of nitric oxide, vascular endothelial growth factor-A, and proinflammatory agents. Concurrently, A?s•CaSR signaling hinders the release of soluble (s)APP-? peptide, a neurotrophic agent and GABABR1a agonist. Altogether these effects progressively kill human cortical neurons in vitro and likely also in vivo. Several CaSR's negative allosteric modulators suppress all the noxious effects elicited by A?s•CaSR signaling in human cortical astrocytes and neurons thus safeguarding neurons' viability in vitro and raising hopes about their potential therapeutic benefits in AD patients. Further basic and clinical investigations on these hot topics are needed taking always heed that activation of the several brain family C GPCRs may elicit divergent upshots according to the models studied.

Dataset Information

Perspective: Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors.

Publications

Perspective: Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors.

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