[I-125] IODOPROXYFAN AND RELATED-COMPOUNDS - A REVERSIBLE RADIOLIGANDAND NOVEL CLASSES OF ANTAGONISTS WITH HIGH-AFFINITY AND SELECTIVITY FOR THE HISTAMINE HS RECEPTOR

Citation
H. Stark et al., [I-125] IODOPROXYFAN AND RELATED-COMPOUNDS - A REVERSIBLE RADIOLIGANDAND NOVEL CLASSES OF ANTAGONISTS WITH HIGH-AFFINITY AND SELECTIVITY FOR THE HISTAMINE HS RECEPTOR, Journal of medicinal chemistry, 39(6), 1996, pp. 1220-1226
Citations number
42
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
39
Issue
6
Year of publication
1996
Pages
1220 - 1226
Database
ISI
SICI code
0022-2623(1996)39:6<1220:[IAR-A>2.0.ZU;2-5
Abstract
The synthesis and biological evaluation of new histamine H-3 receptor antagonists with an iodinated aryl partial structure are described as part of an extensive research program to find model compounds for the development of a new radioligand with high H-3 receptor affinity and s pecific activity. All compounds were tested for their H-3 receptor ant agonist activity in a [H-3]-histamine-release assay with synaptosomes from rat cerebral cortex. The new leads with potent H-3 receptor antag onist activity belong to a series of derivatives of 3-(1H-imidazol-4-y l)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as fu nctional groups. Structure-activity relationships are discussed. The m ost active compound in the functional test (-log K-i = 8.3) and in bin ding studies with [H-3]-(R)-alpha-methylhistamine on rat cerebral cort ex (-log K-i = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl(4-iodophen l)methyl ether (iodoproxyfan, 19) exhibiting no central H-3 receptor a ntagonist activity in vivo. The potency of iodopruxyfan is more than 3 00 times lower at H-1, H-2, alpha(1), alpha(2), beta(1), 5-HT2A, 5-HT3 , and M(3) receptors than at histamine H-3 receptors. Because of the h igh potency and selectivity of 19, this compound has also been prepare d in the [I-125]-iodinated form by a nucleophilic halogen exchange rea ction using the corresponding bromo derivative 22 as a precursor. The newly prepared [I-125]iodoproxyfan (23) possesses advantageous pharmac ological properties and fulfills all criteria of a useful radioligand.