ABSTRACT
A high yielding three-step procedure was applied for the synthesis of N-(imidazolidin-2-ylidene)-1-arylmethanamine oxides 3 (α-aminonitrones) starting from the easily accessible imidazolidin-2-one O-benzyl oxime 1. The α-aminonitrone-α-iminohydroxyloamine tautomerism of these products was studied theoretically and the structures of the synthesised compounds were confirmed by single crystal X-ray crystallographic analysis. The compounds were evaluated in vitro for their binding affinities to α(1) and α(2) adrenoceptors as well as imidazoline I(1) and I(2) receptors. The highest potencies at the α(2) adrenergic receptors were observed for compounds bearing biphenyl (4h, K(i) = 9 nM) and naphthyl (4i, K(i) = 92 nM) moieties. Compounds 4h and 4i were further tested in vivo for their cardiovascular and sedative-hypnotic effects in rats.
Subject(s)
Drug Design , Hydroxylamines/chemical synthesis , Imidazolines/chemical synthesis , Oxides/chemical synthesis , Animals , Brain/drug effects , Brain/metabolism , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Hydroxylamines/chemistry , Hydroxylamines/pharmacology , Imidazoline Receptors/metabolism , Imidazolines/chemistry , Imidazolines/pharmacology , Male , Models, Molecular , Molecular Structure , Oxides/chemistry , Oxides/pharmacology , Protein Binding , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 2-[(heteroaryl)methyl]imidazolines was synthesized and tested for their activities at α(1)- and α(2)-adrenoceptors and imidazoline I(1) and I(2) receptors. The most active 2-[(indazol-1-yl)methyl]imidazolines showed high or moderate affinities for α(1)- and α(2)-adrenoceptors. However, their intrinsic activities at α(2A)-adrenoceptors proved to be negligible. A selected 7-chloro derivative behaved as a potent α(1)-adrenoceptor antagonist and exhibited peripherally mediated hypotensive effects in rats.
Subject(s)
Adrenergic alpha-Antagonists/chemical synthesis , Imidazolines/chemistry , Adrenergic alpha-Antagonists/chemistry , Adrenergic alpha-Antagonists/pharmacology , Animals , Blood Pressure/drug effects , Heart Rate/drug effects , Humans , Imidazolines/chemical synthesis , Imidazolines/pharmacology , Motor Activity/drug effects , Rats , Receptors, Adrenergic, alpha-1/chemistry , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Adrenergic, alpha-2/chemistry , Receptors, Adrenergic, alpha-2/metabolism , Structure-Activity RelationshipABSTRACT
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.
