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Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT2C Receptor Agonist.

ABSTRACT: The development of probe molecules that can be used to investigate G protein-coupled receptor (GPCR) pharmacology, trafficking, and relationship with other GPCRs is an important and growing area of research. Here, we report the synthesis of analogues of the known selective serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonist WAY163909 which were designed to allow for the attachment of a second ligand, signaling or reporter molecules, as well as immobilization agents to the parent molecule with the maintenance of agonist activity. This goal was accomplished by the synthesis of novel molecules in which sites a-d were modified and resulting compounds were analyzed pharmacologically in vitro.

SUBMITTER: Chen YC

PROVIDER: S-EPMC5664164 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT2C Receptor Agonist.

Chen Ying-Chu YC Hartley Rachel M RM Anastasio Noelle C NC Cunningham Kathryn A KA Gilbertson Scott R SR

ACS chemical neuroscience 20170419 5

The development of probe molecules that can be used to investigate G protein-coupled receptor (GPCR) pharmacology, trafficking, and relationship with other GPCRs is an important and growing area of research. Here, we report the synthesis of analogues of the known selective serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonist WAY163909 which were designed to allow for the attachment of a second ligand, signaling or reporter molecules, as well as immobilization agents to the pa ...[more]

PMID: 28414422

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Project description:Mitochondria play a central role in metabolic homeostasis, and dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Tetrapeptides with alternating cationic and aromatic residues such as SS-31 (elamipretide) show promise as therapeutic compounds for mitochondrial disorders. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs, benchmarked against SS-31, that differ with respect to aromatic side chain composition and sequence register. We present the first structural models for this class of compounds, obtained with Nuclear Magnetic Resonance (NMR) and molecular dynamics approaches, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. The peptides had no strict requirement for side chain composition or sequence register to permeate cells and target mitochondria in mammalian cell culture assays. All four peptides were pharmacologically active in serum withdrawal cell stress models yet showed significant differences in their abilities to restore mitochondrial membrane potential, preserve ATP content, and promote cell survival. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register influence the activity of these mitochondria-targeted peptides, helping provide a framework for the rational design of next-generation therapeutics with enhanced potency.

Dataset Information

Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT2C Receptor Agonist.

Publications

Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT<sub>2C</sub> Receptor Agonist.

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