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Related Concept Videos

Drug-Receptor Interaction: Agonist01:25

Drug-Receptor Interaction: Agonist

Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
Adrenergic Agonists: Indirect-Acting Agents01:25

Adrenergic Agonists: Indirect-Acting Agents

Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...
Chemotherapy-Induced Nausea and Vomiting: Dopamine Receptor Antagonists01:29

Chemotherapy-Induced Nausea and Vomiting: Dopamine Receptor Antagonists

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.
Phenothiazines, such as prochlorperazine...
Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers01:17

Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers

Adrenergic antagonists, or sympatholytics, inhibit adrenoceptor activation driven by catecholamines or agonists. Based on their adrenoceptor specificity, adrenergic blockers can be categorized into two primary groups: α-adrenergic blockers (α-blockers) and β-adrenergic blockers (β-blockers). α-blockers interact with α1 and α2 subtypes of α-adrenoceptors.
Nonselective α-blockers: Nonselective α-blockers contain haloalkylamine or imidazoline moieties. Phenoxybenzamine, with a haloalkylamine...
Antipsychotic Drugs: Typical and Atypical Agents01:21

Antipsychotic Drugs: Typical and Atypical Agents

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...
Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...

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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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Published on: August 16, 2018

Aminopyrazine CB1 receptor inverse agonists.

David J Wustrow1, George D Maynard, Jun Yuan

  • 1Neurogen Corporation, 35 Northeast Industrial Road, Branford CT 06405, USA. dwustrow@nrgn.com

Bioorganic & Medicinal Chemistry Letters
|May 2, 2008
PubMed
Summary

Researchers developed novel CB1 receptor antagonists, 5,6-diaryl-2-amino-pyrazines. Optimized compounds showed inverse agonism, inhibiting food intake and occupying central CB1 receptors in vivo.

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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

Published on: June 13, 2022

Area of Science:

  • Medicinal Chemistry
  • Neuropharmacology
  • Obesity Research

Background:

  • The endocannabinoid system, particularly the cannabinoid receptor type 1 (CB1), plays a crucial role in regulating appetite and energy balance.
  • CB1 receptor antagonists have emerged as potential therapeutic agents for obesity and metabolic disorders.
  • Developing selective and safe CB1 modulators with improved pharmacokinetic profiles remains a significant challenge.

Purpose of the Study:

  • To synthesize and characterize a novel series of 5,6-diaryl-2-amino-pyrazines as potential CB1 receptor modulators.
  • To optimize the lead compounds for enhanced receptor potency, selectivity, and drug-like properties, including solubility and metabolic stability.
  • To evaluate the in vivo efficacy of optimized compounds as inverse agonists in preclinical models of obesity.

Main Methods:

  • Synthesis of 5,6-diaryl-2-amino-pyrazine analogs.
  • In vitro evaluation of receptor binding affinity and functional activity at the CB1 receptor.
  • Structure-activity relationship (SAR) studies to guide optimization of potency and pharmacokinetic properties.
  • In vivo studies in rodent models to assess food intake, CB1 receptor occupancy, and hormonal changes.

Main Results:

  • A series of 5,6-diaryl-2-amino-pyrazines were synthesized and exhibited antagonist-like properties at the CB1 receptor.
  • Structure-activity relationship studies led to optimized compounds with improved CB1 receptor potency and favorable drug-like properties (e.g., solubility, reduced CYP450 inhibition).
  • Optimized compounds demonstrated inverse agonism at the CB1 receptor and showed efficacy in reducing food intake, occupying central CB1 receptors, and modulating obesity-associated hormonal markers in vivo, comparable to rimonabant.

Conclusions:

  • 5,6-diaryl-2-amino-pyrazines represent a promising chemical class for developing novel CB1 receptor inverse agonists.
  • Optimization of these compounds resulted in molecules with potent CB1 receptor inverse agonism and improved pharmacokinetic profiles.
  • These findings support the potential therapeutic utility of these novel compounds in the management of obesity and related metabolic conditions.