Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands.
Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I1 and I2) and alpha-adrenergic (alpha1 and alpha2) receptor ligands. Their pKi values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases alpha-adrenergic affinity. I1 sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(2'-methoxyphenyl)-imidazoline (17) is one of the best I1 ligands ever reported (pKi = 8.53 and I1/I2 > 3388). On the other hand, I2 selectivity increases in the presence of a methyl group in the para position. The original compound, 2-(3'-fluoro-4'-tolyl)-imidazoline (31) is a new potent ligand for the I2 sites with high selectivity (pKi = 8.53 and I2/I1 > 3388).
Anastassiadou
M
M
Laboratoire de Chimie Pharmaceutique, Université Paul Sabatier, Faculté de Pharmacie 35, Toulouse, France.
Danoun
S
S
Crane
L
L
Baziard-Mouysset
G
G
Payard
M
M
Caignard
D H
DH
Rettori
M C
MC
Renard
P
P
D000311:Adrenal Glands / Q000648:ultrastructure; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000378:metabolism; D001665:Binding Sites; D002417:Cattle; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002540:Cerebral Cortex / Q000648:ultrastructure; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D054755:Imidazoline Receptors; D007672:Kidney Cortex / Q000648:ultrastructure; D008024:Ligands; D011817:Rabbits; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug