RGD Reference Report - Search for histamine H3 receptor antagonists with combined inhibitory potency at Ntau-methyltransferase: ether derivatives. - Rat Genome Database

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Search for histamine H3 receptor antagonists with combined inhibitory potency at Ntau-methyltransferase: ether derivatives.

Authors: Apelt, J  Grassmann, S  Ligneau, X  Pertz, H H  Ganellin, C R  Arrang, J M  Schwartz, J C  Schunack, W  Stark, H 
Citation: Apelt J, etal., Pharmazie. 2005 Feb;60(2):97-106.
RGD ID: 152985534
Pubmed: PMID:15739896   (View Abstract at PubMed)

With the recent development of new hybrid compounds having histamine H3 receptor antagonist with combined histamine Ntau-methyltransferase (HMT) inhibitory potency an innovative approach was described in the research of novel lead compounds modulating histaminergic neurotransmission. Several compounds containing an ether moiety derived from the recently published 4-(3-piperidinopropoxy)phenylaminoquinoline derivatives (like FUB 836), were synthesized in this study and tested for their affinity at cloned human histamine H3 (hH3) receptors and on the inhibition of rat HMT. Besides different heterocycles, e.g. nitro- or amino-substituted pyridines, quinolines, benzothiazole or pyrroline, three classes of compounds were produced: heteroaromatic 3-piperidinopropyl ethers, keto- or imino-substituted 4-(3-piperidinopropyl)phenyl ethers and 4-(3-piperidinopropyl)phenyl ethers with substituted (alkyl)aminopyridines. Whereas the (3-piperidinopropoxy)heterocycles showed only moderate activities on both test models, the 4-(3-piperidinopropoxy)phenyl derivatives were identified as potent histamine H3 receptor ligands and/or HMT inhibitors. Ki values up to 0.42 nM were found for the affinity to the hH3 receptor. HMT inhibitory potency was identified with IC50 values about 0.3 microM for the most potent compounds in this series. Comparison of the pyridine-containing derivatives to recently published quinoline analogues showed a decrease in potencies for the pyridines. The dual activity, H3 receptor affinity and HMT inhibition, was moderate to good. For all compounds affinities at hH3 receptors were higher than their inhibitory HMT potencies. The described new histamine H3 receptor antagonists with an ether moiety represent a further promising step in our investigations for a dual activity.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
histamine metabolic process  IDA 152985534 RGD 
S-adenosylmethionine metabolic process  IDA 152985534 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
histamine N-methyltransferase activity  IDA 152985534 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hnmt  (histamine N-methyltransferase)


Additional Information