Importance of the lipophilic group in carbamates having histamine H3-receptor antagonist activity.
In order to evaluate changes in the lipophilic part of designed carbamates concerning their potential histamine H3-receptor antagonist properties a new series of O-[3-(1H-imidazol-4-yl)propanol]carbamates was derived containing N-mono- or di-alkenyl, alkynyl, cycloalkyl, or double-branched alkyl substituents. The compounds were tested in vitro for their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex and shared moderate to high antagonist activity in vitro. In this series 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate (4) was the most potent compound in vitro (Ki = 6.3 nM). H3-receptor antagonist activity in the central nervous system (CNS) was detected for most compounds in the in vivo H3-receptor assay based upon measurement of brain N tau-methylhistamine levels after p.o. administration to mice. The most effective carbamate in vivo, 3-(1H-imidazol-4-yl)propyl N-(allyl)carbamate (3), showed higher CNS potency (ED50 = 0.48 mg/kg p.o.) than the reference antagonist thioperamide. For some novel carbamates their histamine H1- and H2-receptor activities were determined on isolated organs of guinea-pig thereby demonstrating their high H3-receptor selectivity.
Kieć-Kononowicz
K
K
Department of Chemical Technology of Drugs, Collegium Medicum of the Jagiellonian University, Kraków, Poland.
Wiecek
M
M
Sasse
A
A
Ligneau
X
X
Elz
S
S
Ganellin
C R
CR
Schwartz
J C
JC
Stark
H
H
Schunack
W
W
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002219:Carbamates; D006633:Histamine Antagonists; D007202:Indicators and Reagents; D018100:Receptors, Histamine H3