PT  - JOURNAL ARTICLE
AU  - Lyne Fellmann
AU  - Véronique Regnault
AU  - Hugues Greney
AU  - Vincent Gasparik
AU  - Adeline Muscat
AU  - Jean-Pierre Max
AU  - Luc Gigou
AU  - Valérie Oréa
AU  - Gérard Chetrite
AU  - Anne Pizard
AU  - Nathalie Niederhoffer
AU  - Claude Julien
AU  - Patrick Lacolley
AU  - Bruno Fève
AU  - Pascal Bousquet
TI  - A New Pyrroline Compound Selective for I<sub>1</sub>-Imidazoline Receptors Improves Metabolic Syndrome in Rats
AID  - 10.1124/jpet.113.205328
DP  - 2013 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 370--380
VI  - 346
IP  - 3
4099  - http://jpet.aspetjournals.org/content/346/3/370.short
4100  - http://jpet.aspetjournals.org/content/346/3/370.full
SO  - J Pharmacol Exp Ther2013 Sep 01; 346
AB  - 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 [125I]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.