Acidic elements in histamine H(3) receptor antagonists.
Antagonists of the human histamine H(3) receptor (hH(3)R) often contain a second basic moiety, which is well known to boost affinity on this histamine receptor subtype. Here, we prepared compounds with acidic moieties of different pK(a) values to figure out that the hH(3)R tolerates these functionalities when added to a common pharmacophore blueprint. Depending on the acidic, electronic and steric features the designed ligands showed hH(3)R affinities in the nanomolar concentration range. Additionally, selected ligands were tested but failed as dual acting hH(3)R/hPPAR (human peroxisome proliferator-activated receptor) ligands.
Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, ZAFES/LiFF/CMP, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
Kerstin
K
Sander
Yvonne
Y
von Coburg
Jean-Claude
JC
Camelin
Xavier
X
Ligneau
Oliver
O
Rau
Manfred
M
Schubert-Zsilavecz
Jean-Charles
JC
Schwartz
Holger
H
Stark
D000143:Acids / Q000737:chemistry*; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000143:Acids; D006633:Histamine Antagonists; D008024:Ligands; D047495:PPAR gamma; D018100:Receptors, Histamine H3