Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 1. Synthesis and biological activities of N-benzyl-N'-(arylalkyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines .
The physiopathology of non-insulin-dependent diabetes mellitus is associated with a dysfunction in the regulation of insulin secretion. The alpha 2-adrenoceptors have been reported to be involved in this alteration, although alpha 2-antagonists containing an imidazoline ring may stimulate insulin secretion independently of alpha 2-adrenoceptor blockage. Recently, a new "imidazoline-binding site" involved in the control of K(+)-ATP channels in the B cell has been proposed. In the course of searching for new antidiabetic agents, 1-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines, 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-alkylpiperazines, and 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines have been designed and evaluated as potential adrenoceptor antagonists. Pharmacological evaluation was performed in vivo using glucose tolerance tests performed on a rat model of type II diabetes obtained by injection of a low dose (35 mg/kg) of streptozotocin (STZ). For some compounds, binding experiments were performed on alpha 2 adrenoceptors and I1 and I2 imidazoline-binding sites. The biological and physicochemical data have been combined with molecular modeling studies to establish structure-activity relationships. The most active compound was 1-(2',4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)- 4-methylpiperazine (7f); intraperitoneal administration (100 mumol/kg) of 7f strongly improved glucose tolerance in STZ diabetic rats. This effect seemed at least partly mediated by a significant increase of insulin secretion. Other compounds of the same family (7b, 16f, 23b) have also shown potent activity. We found no correlation between in vivo antihyperglycemic properties and in vitro affinities for alpha 2-adrenoceptors or I1, and I2 binding sites. These compounds can be considered as antihyperglycemic agents potentially useful for treatment of type II diabetes and are currently under complementary investigation.
Rondu
F
F
Laboratoire de Pharmacochimie Moléculaire, CNRS URA 307, Université Paris 7-Denis Diderot, France.
Le Bihan
G
G
Wang
X
X
Lamouri
A
A
Touboul
E
E
Dive
G
G
Bellahsene
T
T
Pfeiffer
B
B
Renard
P
P
Guardiola-Lemaitre
B
B
Manechez
D
D
Penicaud
L
L
Ktorza
A
A
Godfroid
J J
JJ
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism
D001786:Blood Glucose; D007093:Imidazoles; D010879:Piperazines; D018341:Receptors, Adrenergic, alpha-2