Kleinmaier, Roland and Keller, Max and Igel, Patrick and Buschauer, Armin and Gschwind, Ruth M. (2010) Conformations, Conformational Preferences, and Conformational Exchange of N '-Substituted N-Acylguanidines: Intermolecular Interactions Hold the Key. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 132 (32). pp. 11223-11233. ISSN 0002-7863,
Full text not available from this repository. (Request a copy)Abstract
Guanidine and acylguanidine groups are crucial structural features of numerous biologically active compounds. Depending on the biological target, acylguanidines may be considered as considerably less basic bioisosteres of guanidines with improved pharmacokinetics and pharmacodynamics, as recently reported for N'-monoalkylated N-acylguanidines as ligands of G-protein-coupled receptors (GPCRs). The molecular basis for enhanced ligand receptor interactions of acylguanidines is far from being understood. So far, only a few and contradictory results about their conformational preferences have been reported. In this study, the conformations, conformational preferences, and conformational exchange of four unprotonated and seven protonated monoalkylated acylguanidines with up to six anions and with bisphosphonate tweezers are investigated by NMR. Furthermore, the effects of the acceptor properties in acylguanidine salts, of microsolvation by dimethylsulfoxide, and of varying acyl and alkyl substituents are studied. Throughout the whole study, exclusively two out of eight possible acylguanidine conformations were detected, independent of the compound, the anion, or the solvent used. For the first time, it is shown that the strength and number of intermolecular interactions with anions, solvent molecules, or biomimetic receptors decide the conformational preferences and exchange rates. One recently presented and two new crystal structures resemble the conformational preferences observed in solution. Thus, consistent conformational trends are found throughout the structurally diverse compound pool, including two potent GPCR ligands, different anions, and receptors. The presented results may contribute to a better understanding of the mechanism of action at the molecular level and to the prediction and rational design of these biologically active compounds.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | G-ACYLATED IMIDAZOLYLPROPYLGUANIDINES; ARTIFICIAL ARGININE RECEPTOR; NUCLEAR MAGNETIC-RESONANCE; HYDROGEN-BONDS; AMILORIDE; BINDING; INHIBITORS; PREORGANIZATION; SPECTROSCOPY; SELECTIVITY; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) Chemistry and Pharmacy > Institut für Organische Chemie > Arbeitskreis Prof. Dr. Ruth Gschwind |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Jul 2020 09:43 |
| Last Modified: | 15 Jul 2020 09:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/24319 |
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