Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 19, Issue 1, Pages 321-329Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.11.020
Keywords
Imidazolines; Indazoles; Alpha2-adrenenoceptor agonists; Hypotensive agents; Synthesis; X-ray structure
Funding
- Polish Ministry of Science and Higher Education, Poland [N40500532/0458]
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A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective alpha(2)-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display alpha(2)-adrenoceptor affinity at nanomolar concentrations (K-i = 39.4, 15.9 and 22.6 nM, respectively) and relatively high alpha(2)/I-1 selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at alpha(2A)-adrenoceptors. Compound 4d with intrinsic activity comparable with that of marsanidine, but lower than that of clonidine, elicited pronounced cardiovascular effects in anesthetized rats at doses as low as 0.01 mg/kg iv (C) 2010 Elsevier Ltd. All rights reserved.
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