4- or 5- (omega-aminoalkyl) thiazoles and derivatives; new selective H2-receptor agonists.
It is well known that both histamine and dimaprit show moderate H2-receptor agonistic activity (guinea pig right atrium). Quantum chemical calculations indicated that 2-aminothiazole derivatives that might be regarded as cyclic dimaprit analogues, should possess H2-receptor agonistic activity as well. In the present study a series of 4- or 5-(omega-aminoalkyl) thiazoles has been synthesized, showing a moderate to strong H2-receptor agonistic activity as compared to histamine whereas no activity on H1- and H3-receptors could be detected. In contrast to histamine and derivatives, which are supposed to "trigger" the H2-receptor via a tautomeric shift involving two protons viz. one proton of the active site of the receptor and one proton of the heteroaromatic ring system, the thiazole derivatives seem to stimulate the H2-receptor via a one proton mechanism. In a series of impromidine analogues the 3- [4(5)-imidazolyl]propyl moiety was replaced by the more H2-receptor specific 3-(4- or 5-thiazolyl)propyl fragment resulting in potent and selective full H2-receptor agonists.
Eriks
J C
JC
Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Sterk
G J
GJ
van der Aar
E M
EM
van Acker
S A
SA
van der Goot
H
H
Timmerman
H
H
D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D017446:Impromidine; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
D000588:Amines; D006146:Guanidines; D007093:Imidazoles; D011970:Receptors, Histamine H2; D013844:Thiazoles; D006632:Histamine; D017446:Impromidine