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

With the recent development of new hybrid compounds having histamine H 3 receptor antagonist with combined histamine N τ -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 H 3 (hH 3 ) 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 iminosubstituted 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 H 3 receptor ligands and/or HMT inhibitors. Kj values up to 0.42 nM were found for the affinity to the hH 3 receptor. HMT inhibitory potency was identified with IC 5 0 values about 0.3 μM 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, H 3 receptor affinity and HMT inhibition, was moderate to good. For all compounds affinities at hH 3 receptors were higher than their inhibitory HMT potencies. The described new histamine H 3 receptor antagonists with an ether moiety represent a further promising step in our investigations for a dual activity.