Journal article
"Methylene Bridge" to 5-HT3 Receptor Antagonists: Conformationally Constrained Phenylguanidines
ACS chemical neuroscience, v 10(3), pp 1380-1389
01 Mar 2019
PMID: 30375852
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT3 receptors (e.g., partial agonist, agonist, superagonist). Here, we demonstrate that conformational constraint of these agents as dihydroquinazolines (such as A6CDQ; 1) results in their conversion to 5-HT3 receptor antagonists. We examined the structure activity relationships of 1. Replacement/removal of any of the guanidinium nitrogen atoms of 1 resulted in decreased affinity. All three nitrogen atoms of 1 are necessary for optimal binding affinity at 5-HT3 receptors. Introduction of substituents as small as an N2-methyl group abolishes affinity. The results are consistent with homology modeling/docking studies and binding data from site-directed mutagenesis studies. Introducing a "methylene bridge" to the arylguanidine structure, regardless of its functional activity, results in a 5-HT3 receptor antagonist.
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Details
- Title
- "Methylene Bridge" to 5-HT3 Receptor Antagonists: Conformationally Constrained Phenylguanidines
- Creators
- Ahmed S. Ahdelkhalek - Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, POB 980540, Richmond, VA 23298 USAGenevieve S. Alley - Virginia Commonwealth UniversityOsama I. Alwassil - Virginia Commonwealth UniversityShailesh Khatri - University of the SciencesPhilip D. Mosier - Virginia Commonwealth UniversityHeather L. Nyce - Drexel UniversityMichael M. White - Drexel UniversityMarvin K. Schulte - University of the SciencesMalgorzata Dukat - Virginia Commonwealth University
- Publication Details
- ACS chemical neuroscience, v 10(3), pp 1380-1389
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 19
- Grant note
- Egyptian Channel Program VCU Presidential Research Quest Fund RG J-778 / Jeffress Memorial Trust Egyptian Cultural and Educational Bureau; Egyptian Cultural & Educational Bureau A. D. Williams Trust funds
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000462259900044
- Scopus ID
- 2-s2.0-85056457396
- Other Identifier
- 991019168883504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Neurosciences