Piperidine-containing histamine H3 receptor antagonists of the carbamate series: the alkyl derivatives.
A series of N-alkyl urethanes, potential histamine H3 receptor antagonists, was prepared. Carbamate derivatives were synthesized from appropriate isocyanates and N-piperidinoalkan-1-ols. The novel compounds were evaluated for histamine H3 receptor activity in vitro on the guinea pig ileum. Some selected compounds were tested in vivo after p.o. application to mice and in vitro for selectivity towards other histamine receptors (H1, H2) in functional assays in the guinea pig. The most potent H3 receptor antagonist in vitro was compound 14 (pA2 = 7.2). Compound 14 was equipotent at M3 receptors and lacked H3 receptor activity in vivo. Predictions of octanol-water partition coefficient (Pallas) and metabolic fate (MetabolExpert, METEOR) were used to explore potential reasons for this absence of in vivo activity.
Lazewska
D
D
Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University, Kraków, Poland.
Kieć-Kononowicz
K
K
Elz
S
S
Pertz
H H
HH
Stark
H
H
Schunack
W
W
D000818:Animals; D001711:Biotransformation; D002219:Carbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D043587:Receptor, Muscarinic M3 / Q000187:drug effects; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000187:drug effects*
D002219:Carbamates; D006633:Histamine Antagonists; D007202:Indicators and Reagents; D010880:Piperidines; D043587:Receptor, Muscarinic M3; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3