3-[(Imidazolidin-2-yl)imino]indazole ligands with selectivity for the α(2)-adrenoceptor compared to the imidazoline I(1) receptor.
A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective α(2)-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display α(2)-adrenoceptor affinity at nanomolar concentrations (K(i)=39.4, 15.9 and 22.6nM, respectively) and relatively high α(2)/I(1) selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at α(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 0.01mg/kg iv.
Department of Chemical Technology of Drugs, Medical University of Gdańsk, 80-416 Gdańsk, Poland. saczew@gumed.edu.pl
Franciszek
F
Sączewski
Anita
A
Kornicka
Alan L
AL
Hudson
Shayna
S
Laird
Mika
M
Scheinin
Jonne M
JM
Laurila
Apolonia
A
Rybczyńska
Konrad
K
Boblewski
Artur
A
Lehmann
Maria
M
Gdaniec
D000818:Animals; D054755:Imidazoline Receptors / Q000378:metabolism*; D007191:Indazoles / Q000737:chemistry*; D008024:Ligands; D011869:Radioligand Assay; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
D054755:Imidazoline Receptors; D007191:Indazoles; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; C410887:imidazoline I1 receptors