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Chemotherapy-Induced Nausea and Vomiting: Dopamine Receptor Antagonists01:29

Chemotherapy-Induced Nausea and Vomiting: Dopamine Receptor Antagonists

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Dopamine receptor antagonists, also known as antipsychotic agents, are critical in managing chemotherapy-induced vomiting. These antiemetic agents block dopamine receptors in the chemoreceptor trigger zone (CTZ), inhibiting signal transmission to the vomiting center. Antipsychotic agents encompass phenothiazines (PTZ), butyrophenones, benzamides, and thienobenzodiazepines (Zyprexa), which are utilized for their antiemetic and sedative properties.
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Neurokinin 1 (NK1) receptors are distributed across the GI tract, vagal afferents, and key CNS regions including the central vomiting center and chemoreceptor trigger zone (CTZ) Chemotherapy agents stimulate enterochromaffin cells in the gastrointestinal (GI) tract to release large amounts of substance P (SP). SP is a neuropeptide released by specific sensory nerves in response to many different stressors, including those in the GI mucosa affected by chemotherapy.  SP binds and activates...
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Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists01:23

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Prostacyclin receptor agonists are a class of therapeutic agents integral to managing pulmonary arterial hypertension (PAH). These drugs operate by mimicking the action of prostaglandin I2, or PGI2, a naturally occurring compound in the body.
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
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Chemotherapy-Induced Nausea and Vomiting: 5-HT3 Receptor Antagonists01:27

Chemotherapy-Induced Nausea and Vomiting: 5-HT3 Receptor Antagonists

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5-HT3 receptor antagonists, such as dolasetron, granisetron (Kytril), ondansetron (Zofran), and palonosetron (Axoli), are crucial in managing chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea. These drugs selectively block 5-HT3 receptors in the visceral vagal and spinal afferent nerves, chemoreceptor trigger zone, and the vomiting center. They have a rapid onset of action and can be given as a single dose before chemotherapy. Ondansetron and granisetron, in particular,...
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Antipsychotic Drugs: Typical and Atypical Agents01:21

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Antipsychotic drugs are classified into first-generation (typical) drugs including phenothiazines; and second-generation (atypical) drugs. Chlorpromazine hydrochloride (Thorazine), a phenothiazine derivative, broadly impacts the central, autonomic, and endocrine systems. This drug, along with typical agents like haloperidol (Haldol), primarily works by antagonizing D2 receptors, thus reducing dopaminergic neurotransmission. However, typical antipsychotics can cause side effects such as sedation...
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Chemotherapy-Induced Nausea and Vomiting: Cannabinoids01:21

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Tetrahydrocannabinol (THC) is a phytocannabinoid that primarily interacts with the CB1 receptor, a type of G protein-coupled receptor (GPCR) predominantly in and around the chemoreceptor trigger zone (CTZ) and emetic center. THC also blocks the serotonin receptor activity in the dorsal vagal complex (DVC) by inhibiting serotonin release. THC exerts its anti-emetic effects through these interactions, which are beneficial for patients undergoing chemotherapy.
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Spiropiperidine CCR5 antagonists.

David M Rotstein1, Stephen D Gabriel, Ferenc Makra

  • 1Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. david.rotstein@roche.com

Bioorganic & Medicinal Chemistry Letters
|August 14, 2009
PubMed
Summary
This summary is machine-generated.

Researchers developed novel CCR5 antagonists by refining high-throughput screening leads and competitor data. Lead optimization balanced metabolic stability and potency, yielding selective analogs with favorable pharmacokinetics.

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Area of Science:

  • Medicinal Chemistry
  • Drug Discovery
  • Pharmacology

Background:

  • Chemokine receptor type 5 (CCR5) antagonists are crucial in treating viral infections and inflammatory diseases.
  • Existing CCR5 antagonist development faces challenges in balancing efficacy and pharmacokinetic profiles.

Purpose of the Study:

  • To identify and optimize novel CCR5 antagonists with improved therapeutic potential.
  • To overcome limitations of current CCR5 antagonists through strategic lead modification.

Main Methods:

  • High-throughput screening (HTS) was employed to identify initial lead compounds.
  • Lead compounds were structurally modified incorporating insights from competitor molecules.
  • Structure-activity relationship (SAR) studies guided optimization for potency and metabolic stability.

Main Results:

  • A novel series of potent CCR5 antagonists was successfully identified.
  • Lead optimization effectively balanced metabolic stability and target potency.
  • Developed analogs demonstrated selective CCR5 antagonism with promising pharmacokinetic properties.

Conclusions:

  • The study successfully generated novel, optimized CCR5 antagonists.
  • These compounds represent promising candidates for further preclinical and clinical development.
  • The optimization strategy provides a valuable framework for future drug discovery efforts targeting chemokine receptors.