Substituted N-phenylcarbamates as histamine H3 receptor antagonists with improved in vivo potency.
Novel substituted N-phenylcarbamates as derivatives of 3-(1 H-imidazol-4-yl)propanol were prepared and tested for their antagonist potency in vitro and in vivo at histamine H3 receptors. Structural modifications with different alkyl and acetyl moieties were performed in an attempt to optimize pharmacodynamic and pharmacokinetic effects. Most compounds are active in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes as well as in a peripheral model on guinea pig ileum. But only carbamates without too bulky lipophilic residues showed pronounced to high antagonist potency on the enhancement of endogenous histamine in brain after p.o. administration to mice (ED50 values of 5.5 to 0.86 mg.kg-1). The tested compounds presented weak activities at histamine H1, H2, and muscarinic M3 receptors thus demonstrating their H3-receptor selectivity.
Reidemeister
S
S
Institut für Pharmazie, Freie Universität Berlin, Germany.
Stark
H
H
Ligneau
X
X
Ganellin
C R
CR
Schwartz
J C
JC
Schunack
W
W
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D043587:Receptor, Muscarinic M3; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002219:Carbamates; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D008761:Methylhistamines; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D018100:Receptors, Histamine H3; D011976:Receptors, Muscarinic; C031205:3-methylhistamine; C059692:phenylcarbamic acid