Grassmann, Sven and Sadek, Bassem and Ligneau, Xavier and Elz, Sigurd and Ganellin, C. Robin and Arrang, Jean-Michel and Schwartz, Jean-Charles and Stark, Holger and Schunack, Walter (2002) Progress in the proxifan class: heterocyclic congeners as novel potent and selective histamine H-3-receptor antagonists. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 15 (4): PII S0928-. pp. 367-378. ISSN 0928-0987, 1879-0720
Full text not available from this repository. (Request a copy)Abstract
Histamine H-3 receptors are critically involved in the pathophysiology of several disorders of the central nervous system (CNS). Among other families of H-3-receptor ligands, the proxifan class has recently been described to contain numerous potent histamine H-3-receptor antagonists, e,g, ciproxifan or imoproxifan. In the present study, we report on the design of novel heterocyclic proxifan analogues and their antagonist potencies at histamine H-3 receptors. The new compounds were tested for in vitro and in vivo H-3-receptor antagonist potencies in different species as well as for H-3-receptor selectivity vs. H-1 and H-3 receptors. In vitro, all compounds investigated proved to be potent H-3-receptor antagonists in the rat as well as in the guinea-pig. In addition. they shoved good to high oral CNS potency in vivo in mice. Especially, oxadiazole derivatives 24-26 displayed nanomolar antagonist activity in vitro and high potency in vivo (ED50=0.47-0.57 mg/kg). The results show that the additional heteroaromatic moieties might act as bioisosteres of the ketone or oxime moieties of ciproxifan or imoproxifan, respectively. and might cause divergent pharmacokinetic properties. Thus, these novel H-3-receptor antagonists are interesting leads for further development. (C) 2002 Elsevier Science B.V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CENTRAL-NERVOUS-SYSTEM; H-3 RECEPTOR; HIGHLY POTENT; HIGH-AFFINITY; BRAIN; CIPROXIFAN; LIGANDS; CLONING; DERIVATIVES; INHIBITION; histamine; H-3 receptor; proxifan; antagonist; ciproxifan; imoproxifan |
| 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: | 27 Oct 2021 04:40 |
| Last Modified: | 27 Oct 2021 04:40 |
| URI: | https://pred.uni-regensburg.de/id/eprint/40299 |
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