A new pyrroline compound selective for I1-imidazoline receptors improves metabolic syndrome in rats.

Abstract

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the 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 nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [(125)I]para-iodoclonidine 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. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it 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.

• Authors: Lyne Fellmann, Véronique Regnault, Hugues Greney, Vincent Gasparik, Adeline Muscat, Jean-Pierre Max, Luc Gigou, Valérie Oréa, Gérard Chetrite, Anne Pizard, Nathalie Niederhoffer, Claude Julien, Patrick Lacolley, Bruno Fève, Pascal Bousquet
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 346 Issue 3 Pg. 370-80 (Sep 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23818682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (3-chloro-2-methylphenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)amine
• Adiponectin
• Aniline Compounds
• Imidazoline Receptors
• Lipids
• Pyrroles
• pyrroline

Topics

• 3T3-L1 Cells
• Adiponectin (blood, metabolism)
• Aniline Compounds (therapeutic use)
• Animals
• Blood Pressure (drug effects)
• Body Weight (drug effects)
• Glucose Intolerance (drug therapy)
• Glucose Tolerance Test
• Imidazoline Receptors (drug effects)
• Insulin Resistance
• Kidney (innervation)
• Lipids (blood)
• Male
• Metabolic Syndrome (drug therapy)
• Mice
• Pyrroles (pharmacology, therapeutic use)
• Rats
• Rats, Inbred SHR
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Surface Plasmon Resonance
• Sympathetic Nervous System (drug effects)