Serotonin Antagonist Profiling on 5HT2A and 5HT2C Receptors by Nonequilibrium Intracellular Calcium Response Using an Automated Flow-Through Fluorescence Analysis System, HT-PS® 100

Author: Kaler, Gregory ; Okun, Alex ; Otto, Michael ; Okun, Ilya

Characterization of the potencies of agonists and antagonists in cell-based assays can be complicated by nonequilibrium conditions of functional response.The authors assessed the potencies of a series of serotonin (5HT) antagonists by inhibition of intracellular calcium response in HEK 293 cells expressing 5HT_2A or 5HT_2C receptors.An automated system, HT-PS 100, was used to profile the antagonists in two exptl. setups: coadministration of agonist and antagonist to cells and preincubation of the cells with antagonist prior to agonist administration.The authors showed that the antagonist potencies (pIC₅₀ values) determined in the preincubation configuration were close to or exceeded those measured in the coadministration configuration.Closeness of the potencies determined in the two configurations supposedly reflected a rapid antagonist-receptor equilibration, whereas a significantly higher preincubation potency implied slow antagonist dissociation from the receptor.Schild anal. of the inhibition of serotonin-induced cell response by a competitive 5HT_2A antagonist, spiperone, showed a typical competitive inhibition pattern when both the agonist and antagonist were applied simultaneously.Contrary to this, an insurmountable diminishing of the maximal cell response to serotonin was observed when the cells were preincubated with spiperone.The authors conclude that a combination of the coadministration and preincubation exptl. setups is necessary for appropriate mechanistic interpretation and quant. assessment of the antagonist activity when using transient functional readouts.

Genomic targets and structure-based lead discovery

Author: Zamudio, Carlos

The pharmaceutical industry is in the midst of a profound shift in how drug discovery research and development is performed.New technologies in chem., mol. genetics and informatics, along with the advanced disease research programs in academia and biotechnol. industry have accelerated this process.The timeline of drug discovery, from the identification of a potential drug target to the development of a lead compound is shrinking rapidly.Efforts to decipher the genetic codes of humans and model organisms associated with the Human Genome Project and other genome research, are providing researchers with an overwhelming number of disease-related genetic targets.The elucidation of the function and interaction of these genetic targets remains as the great challenge for biol. research.Through an understanding of these systems, the specificity of genetically-validated therapeutic targets will help propel the predict-and-prevent philosophy embraced by the pharmaceutical industry.The benefits of genome information will provide the pharmaceutical industry not only novel therapeutic agents, but also a means to identify optimal patient populations for clin. trials and, consequently, drugs that are tailored to specific genetic profiles.

Proceedings of SPIE-The International Society for Optical Engineering

Functional characterization of naturally expressed G-protein-coupled receptors in mammalian cells using the automated high-throughput pharmacological system HT-PS 100

Author: Goldman, Mark E. ; Okun, Alex ; Anantharam, Vellareddy ; Okun, Ilya ; Otto, Michael ; Kaler, Gregory

In studying the mol. mechanics of stimulation of a receptor and mechanisms of the receptor's interaction with ligands, the widely used approach is to characterize dose- dependent functional responses of stimulation or inhibition of the receptor.Many GPCRs respond to the stimulation by transient changes in cytoplasmic calcium.A time trace of the ligand-evoked 'calcium signal' visualizes the sequence of signaling events taking place after the initial receptor stimulation.It is more important to know how those events depend on the ligand concentrationThis type of data provides ligand affinity profiles together with information about mechanisms of the receptor/ligand interaction, competitive, non-competitive antagonism, full, or partial stimulation.We have developed an automated system, HT-PS 100, for registering continuous concentration-dependent functional responses in real time at the rate of 2 min per dose-response curve.The flow-through fluidics prepares a concentration gradient of the compound and sequentially mixes it with another reagent, agonist or antagonist, and finally with cells.The resulting 'real time' concentration dependent signal is registered with a fluorescence detector.By monitoring calcium mobilization with Fura-2, we have functionally and mechanistically characterized a variety of G protein-coupled receptors, cholinergic, histaminergic, purinergic, endothelin, and bradykinin, endogenously expressed in different cell lines, SK-N-MC, TE671, and DDT₁MF-2.

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