Influence of bulky substituents on histamine h(3) receptor agonist/antagonist properties.
Novel derivatives of 3-(1H-imidazol-4-yl)propanol were designed on the basis of lead compounds belonging to the carbamate or ether series possessing (partial) agonist properties on screening assays of the histamine H(3) receptor. One pair of enantiomers in the series of alpha-methyl-branched chiral carbamates was stereoselectively prepared in high optical yields. Enantiomeric purity was checked by Mosher amide derivatives of precursors and capillary electrophoresis of the final compounds with trimethyl-beta-cyclodextrin as chiral selector, and was determined to be >/=95%. The novel compounds were investigated in various histamine H(3) receptor assays in vitro and in vivo. Some compounds displayed partial agonist activity on synaptosomes of rat brain cortex, whereas others exhibited antagonist properties only. Selected compounds were investigated in [(125)I]iodoproxyfan binding studies on the human histamine H(3) receptor and showed high affinity in the nanomolar concentration range. Under in vivo conditions after oral administration to mice, some of the compounds exhibited partial or full agonist activity in the brain at low dosages. The (S)-enantiomer of one pair of chiral carbamates (9) proved to be the eutomer; thus, the (S)-enantiomer was selected for further pharmacological studies. In a peripheral in vivo test model in rats, measuring the level of inhibition of capsaicin-induced plasma extravasation, (S)-9 again proved its high oral agonist potency with full intrinsic activity (ED(50) values of 0.07-0.1 mg/kg depending on tissue).
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany.
Astrid
A
Sasse
Xavier
X
Ligneau
Agnès
A
Rouleau
Sigurd
S
Elz
C Robin
CR
Ganellin
Jean-Michel
JM
Arrang
Jean-Charles
JC
Schwartz
Walter
W
Schunack
Holger
H
Stark
D000818:Animals; D016466:CHO Cells; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D019075:Electrophoresis, Capillary; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C465466:3-(1H-imidazol-4-yl)propyl N-(1,2,2-trimethylpropyl) carbamate; D002219:Carbamates; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D018100:Receptors, Histamine H3