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Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H(2) Receptor Agonists†
[Image: see text] 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 (H(2)R) agonists with various alkyl spacers were synthesized. Aiming at increase...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical
Society
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130797/ https://www.ncbi.nlm.nih.gov/pubmed/30221224 http://dx.doi.org/10.1021/acsomega.8b00128 |
Sumario: | [Image: see text] 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 (H(2)R) agonists with various alkyl spacers were synthesized. Aiming at increased H(2)R 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 H(2)R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine hH(4)R ligands. |
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