HISTAMINE-H2-RECEPTOR AGONISTS - SYNTHESIS, INVITRO PHARMACOLOGY, AND QUALITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS OF SUBSTITUTED 4-(2-AMINOETHYL)THIAZOLES AND 5-(2-AMINOETHYL)THIAZOLES

It is well known that both histamine and dimaprit show moderate histamine H-2-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 H-2-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 H-1-receptors and is a full but weak agonist on the histamine H-3-receptor with a pD2 value of 4.70, thus showing a marked specificity for histamine H-2-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 H-2-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 H-2-receptor.