A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity and hypertension have been associated with sympathetic hyperactivity. In addition, adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for non-adrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmaco-therapy. LNP599, a new pyrroline derivative displaced the specific [125I] PIC binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters and enzymes. In addition, it can cross the blood brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Acute administration of LNP599 (10 mg/kg i.v.) in anesthetized SD rats, markedly decreased sympathetic activity, causing hypotension and bradycardia. Chronic treatment of SHHF rats with LNP599 (20 mg/kg p.o.) had favorable effects on blood pressure, bodyweight, insulin resistance, glucose tolerance, lipid profile and increased plasma adiponectin. The pyrroline derivative which inhibits sympathetic activity and stimulates adiponectin secretion has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.