Pockes, Steffen and Wifling, David and Keller, Max and Buschauer, Armin and Elz, Sigurd (2018) Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H-2 Receptor Agonists. ACS OMEGA, 3 (3). pp. 2865-2882. ISSN 2470-1343,
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On the basis of the long-known prototypic pharmacophore 3-(1H-imidazol-4-yl) propylguanidine (SK&F 91486, 2), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H-2 receptor (H2R) agonists with various alkyl spacers were synthesized. Aiming at increased H2R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h/gp/rH(2)R. The most potent analogue, the thiazole-type heterodimeric ligand 63 (UR-Po461), was a partial agonist (E-max = 88%) and 250 times more potent than histamine (pEC(50): 8.56 vs 6.16, gpH(2)R, atrium). The homodimeric structures 56 (UR-Po395) and 58 (UR-Po448) exhibited the highest hH(2)R affinities (pK(i): 7.47, 7.33) in binding studies. Dimeric amino(methyl) thiazole derivatives, such as 58, generated an increased hH(2)R selectivity compared to the monomeric analogues, e.g., 139 (UR-Po444). Although monomeric ligands showed up lower affinities and potencies at the H2R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine hH(4)R ligands.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | G-ACYLATED IMIDAZOLYLPROPYLGUANIDINES; HIGH CONSTITUTIVE ACTIVITY; PROTEIN-COUPLED RECEPTORS; IN-VITRO PHARMACOLOGY; H-4 RECEPTOR; MOLECULAR-DYNAMICS; BINDING-SITE; SF9; SYNCHRONIZATION; ANTAGONIST; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Mar 2020 14:44 |
| Last Modified: | 12 Mar 2020 14:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14971 |
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