Histamine H2-receptor agonists. Synthesis, in vitro pharmacology, and qualitative structure-activity relationships of substituted 4- and 5-(2- aminoethyl)thiazoles

Article abstract of DOI:10.1021/jm00095a021

It is well known that both histamine and dimaprit show moderate histamine H₂-receptor agonistic activities on the guinea pig right atrium. Quantum chemical calculations on these two compounds showed similarities in electron distributions and molecular electrostatic potentials (MEP's), which could be extended to rigid analogues [2-amino-5-(2-aminoethyl)thiazoles] of the latter structure. On the base of these results a series of substituted 4- and 5-(2- aminoethyl)thiazoles was synthesized applying small alkyl substitution variations as reported for histamine. 2-Amino-5-(2-aminoethyl)-4- methylthiazole (Amthamine) proved to be the most potent full histamine H₂- receptor agonist on the guinea pig right atrium, being with a pD₂ value of 6.21 slightly more potent than histamine. This compound shows no affinity for H₁-receptors and is a full but weak agonist on the histamine H₃-receptor with a pD₂ value of 4.70, thus showing a marked specificity for histamine H₂-receptors. In the 5-(2-aminoethyl)thiazole series the presence of a 2- amino substituent proved to be not essential for stimulation of the histamine H₂-receptor, leading to the important conclusion that in contrast to histamine, for this series, acceptance of a proton by the thiazole nucleus of the agonist from the active site of the receptor is sufficient for the stimulation of the histamine H₂-receptor.