Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H
Steffen Pockes1, David Wifling1, Max Keller1
1Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
ACS Omega
|September 18, 2018
Summary
Researchers synthesized novel bisalkylguanidine agonists targeting histamine H2 receptors (H2R). Thiazole-based dimeric compounds showed enhanced H2R selectivity and potency, with some monomeric ligands also exhibiting high affinity for histamine H4 receptors.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- The prototypic histamine H2 receptor (H2R) agonist, 3-(1H-imidazol-4-yl)propylguanidine (SK&F 91486), served as a basis for structural modifications.
- Histamine receptors play crucial roles in various physiological processes, making them important drug targets.
Purpose of the Study:
- To synthesize novel monomeric, homodimeric, and heterodimeric bisalkylguanidine derivatives as histamine H2 receptor (H2R) agonists.
- To enhance H2R selectivity by employing a bioisosteric approach, replacing the imidazol-4-yl moiety with alternative heterocyclic systems.
- To evaluate the potency and affinity of the synthesized compounds at H2R and other histamine receptor subtypes.
Main Methods:
- Chemical synthesis of a series of bisalkylguanidine analogues with varying alkyl spacers and heterocyclic moieties (imidazol-1-yl, 2-aminothiazol-5-yl, 2-amino-4-methylthiazol-5-yl).
- Pharmacological evaluation of synthesized compounds as agonists at human, guinea pig, and rat H2 receptors (h/gp/rH2R).
- Binding studies to determine affinities (pKi) for hH2R and functional assays to measure potency (pEC50) and efficacy (Emax).
Main Results:
- All synthesized compounds demonstrated partial or full agonistic activity at H2Rs.
- The thiazole-type heterodimeric ligand 63 (UR-Po461) emerged as the most potent analogue, exhibiting 250-fold greater potency than histamine at gpH2R.
- Dimeric amino(methyl)thiazole derivatives, such as 58 (UR-Po448), displayed higher hH2R affinities and selectivity compared to their monomeric counterparts.
- Certain monomeric ligands, like 129 (UR-Po194) with a short alkyl chain, showed high affinity for the histamine H4 receptor (hH4R).
Conclusions:
- Bioisosteric replacement of the imidazole moiety in bisalkylguanidines can lead to potent and selective H2R agonists.
- Dimeric thiazole-based compounds represent a promising class for developing selective H2R ligands.
- The study identified compounds with potential for targeting both H2R and H4R, suggesting diverse therapeutic applications.
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