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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.
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Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
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Cholinergic antagonists—such as antimuscarinics—are available in oral, topical, ocular, parenteral, and inhalational formulations. Most antimuscarinics are oral formulations,  while scopolamine is available as a topical patch, and ipratropium and tiotropium are available as inhalation aerosols or powders. Atropine, tropicamide, and cyclopentolate are topically instilled in the eye. Most antimuscarinics are lipid-soluble and readily absorbed from the gastrointestinal tract and...
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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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2-Substituted (N)-Methanocarba A3 Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization.

Dilip K Tosh1, Matteo Pavan1, Chunxia Cronin2

  • 1Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States.

ACS Pharmacology & Translational Science
|July 18, 2024
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New (N)-methanocarba adenosine analogues were synthesized and tested as agonists for the A3 adenosine receptor (AR). Certain 2-arylethynyl compounds showed potent A3AR activity and protected against skeletal muscle ischemia in vivo.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Adenosine receptors (ARs) play crucial roles in various physiological processes.
  • A3 adenosine receptor (A3AR) agonists are investigated for therapeutic potential.
  • Methanocarba adenosine analogues offer a rigid scaffold for receptor interaction.

Purpose of the Study:

  • To synthesize and characterize novel 2-aryl and 2-arylethynyl (N)-methanocarba adenosine 5'-methylamides.
  • To evaluate their structure-activity relationships (SAR) at the human and mouse A3AR.
  • To assess their therapeutic efficacy in an in vivo model of peripheral artery disease (PAD).

Main Methods:

  • Chemical synthesis of novel adenosine analogues.
  • In vitro binding assays to determine affinity (Ki) for A3AR.
  • Molecular modeling and dynamics simulations to predict binding poses.
  • Cell-based assays (miniGαi and β-arrestin2 recruitment) to assess functional activity.
  • In vivo studies using a mouse model of skeletal muscle ischemia-reperfusion injury.

Main Results:

  • 2-Arylethynyl analogues exhibited potent A3AR affinity (2-30 nM Ki) and selectivity.
  • Molecular modeling revealed distinct binding conformations for 2-aryl and 2-arylethynyl substituents.
  • Compound 31 (MRS8062) demonstrated high efficacy in functional assays.
  • Rigidified 2-arylethynyl analogues (3a-3c) showed protective effects in a PAD model.

Conclusions:

  • The study expands the SAR for (N)-methanocarba adenosine A3AR agonists.
  • 2-Arylethynyl substitution is favorable for high A3AR affinity and selectivity.
  • Selected analogues demonstrate therapeutic potential for ischemic conditions like PAD.