title: Histamine H2-receptor agonists. Synthesis, in vitro pharmacology, and qualitative structure-activity relationships of substituted 4- and 5-(2-aminoethyl)thiazoles.
abstract: 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.
authors.affiliation: Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Eriks
authors.forename: H
authors.initials: H
authors.lastname: van der Goot
authors.forename: G J
authors.initials: GJ
authors.lastname: Sterk
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
mesh_terms: D000818:Animals; D016275:Atrial Function; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004563:Electrochemistry; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011970:Receptors, Histamine H2; D013844:Thiazoles; C076207:amthamine; D006632:Histamine