Design of Potent Non-Thiourea H3-Receptor Histamine Antagonists

Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesized and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design potent compounds which do not possess the thiourea group of...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-08, Vol.38 (17), p.3342-3350
Main Authors: Ganellin, C. Robin, Hosseini, S. Kiumars, Khalaf, Yasmin S, Tertiuk, Wasyl, Arrang, Jean-Michel, Garbarg, Monique, Ligneau, Xavier, Schwartz, Jean-Charles
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cerebral Cortex - drug effects
Drug Design
Histamine Antagonists - chemical synthesis
Histamine Antagonists - chemistry
Histamine Antagonists - pharmacology
In Vitro Techniques
Medical sciences
Miscellaneous
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Rats
Synaptosomes - drug effects
Thiourea - pharmacology
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Summary:Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesized and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design potent compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. In a short series of open chain thiourea analogues, the optimum chain length for H3-antagonist potency was found to be (CH2)3. Compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side chain amino group in place of thiourea show H3-antagonist activity. Furthermore, when the heterocycle is 2-pyridyl, electron-withdrawing substituents (e.g. NO2, CF3, CO2Me) in the pyridine 5-position increased potency. The synthesis of 4-[4(5)-imidazolyl]piperidine and its conversion into the (trifluoromethyl)pyridyl analogue 5b of thioperamide is described; however, 5b is not as potent as thioperamide. Replacing imidazole by pyridine or substituting imidazole on the remote N considerably reduced potency. Replacing the side-chain NH by S increased potency still further and the most potent compound is 2-([2-[4(5)-imidazolyl]ethyl]thio)-5-nitropyridine (UCL 1199) which has Ki = 4.8 nM.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00017a018