Sasse, Astrid and Ligneau, Xavier and Rouleau, Agnes and Elz, Sigurd and Ganellin, C. Robin and Arrang, Jean-Michel and Schwartz, Jean-Charles and Schunack, Walter and Stark, Holger (2002) Influence of bulky substituents on histamine H-3 receptor agonist/antagonist properties. JOURNAL OF MEDICINAL CHEMISTRY, 45 (18): UNSP JM020. pp. 4000-4010. ISSN 0022-2623
Full text not available from this repository. (Request a copy)Abstract
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 greater than or equal to95%. 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 [I-125]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 (ED50 values of 0.07-0.1 mg/kg depending on tissue).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | IN-VITRO PHARMACOLOGY; MODIFIED CURTIUS REACTION; H-3-RECEPTOR ANTAGONISTS; CONSTITUTIVE ACTIVITY; VIVO ACTIVITY; CAPILLARY-ELECTROPHORESIS; CONVENIENT REAGENT; PARTIAL AGONISTS; HIGH-AFFINITY; BP 2-94; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 Oct 2021 08:36 |
| Last Modified: | 11 Oct 2021 08:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/39962 |
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