Search for histamine H(3) receptor ligands with combined inhibitory potency at histamine N-methyltransferase: omega-piperidinoalkanamine derivatives.
In an effort to design new hybrid compounds with dual properties, i.e. binding affinity at histamine H(3) receptors and inhibitory potency at the catabolic enzyme histamine N(tau)-methyltransferase (HMT), a novel series of 1-substituted piperidine derivatives was synthesized. This alicyclic heterocycle is structurally linked via aminoalkyl spacers of variable lengths to additional aromatic carbo- or hetero-cycles. These new hybrid drugs were pharmacologically evaluated regarding their binding affinities at recombinant human H(3) receptors, stably expressed in CHO cells, and in a functional assay for their inhibitory potencies at rat kidney HMT. All compounds investigated proved to be H(3) receptor ligands with binding affinities in the micro- to nanomolar concentration range despite significant differences in the type of the aromatic moiety introduced. The most potent compound in this series was the quinoline derivative 20 (K(i) = 5.6 nM). Likewise, all new ligands studied showed impressive HMT inhibitory activities. Here, compounds 5, 10, 14 and 18-20 exhibited submicromolar potencies (IC(50) = 0.061-0.56 microM). The aminomethylated quinoline 19 showed almost the same, well balanced nanomolar activities on both targets. In this study, new hybrid compounds with a dual mode biological action were developed. These pharmacological agents are valuable leads for further development and candidates for treatment of histamine-dependent disorders.
Grassmann
Sven
S
Institut für Pharmazie, Institut für Pharmazie, Berlin, Germany.
Apelt
Joachim
J
Ligneau
Xavier
X
Pertz
Heinz H
HH
Arrang
Jean-Michel
JM
Ganellin
C Robin
CR
Schwartz
Jean-Charles
JC
Schunack
Walter
W
Stark
Holger
H
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000473:Alkanes; D000588:Amines; D008024:Ligands; D010880:Piperidines; D018100:Receptors, Histamine H3; D006637:Histamine N-Methyltransferase