To find new compounds selective for purported I1 imidazoline receptors (I1Rs) over I2 imidazoline binding sites (I2BS) and alpha2-adrenoceptors (alpha2ARs), a series of pyrrolinic isosteres of rilmenidine has been prepared and their biological activity at I1Rs, I2BS, and alpha2ARs evaluated. This isosteric replacement provided us with compounds which still bound to I1Rs but not to I2BS nor to alpha2ARs. A limited structure-affinity relationship was generated around the heterocyclic moiety of these ligands. One compound in this series, LNP 509 (1e) [cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine], had no detectable affinity at alpha2ARs yet was capable of lowering blood pressure after central administration. These pyrrolinic analogues constitute a new chemical class of imidazoline related compounds with high selectivity for the I1Rs. They could be used as new tools in the study of I1Rs and in the conception of new centrally acting hypotensive drugs.

Background-Both ␣ 2 -adrenergic and non-␣ 2 -adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP). Methods and Results-LNP 509, which appeared in this study to be devoid of ␣ 2A -adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. Mean arterial pressure decreased by a maximum of 46Ϯ4% and 16Ϯ2%, respectively. In D79N mice, which lack functional ␣ 2A -adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17Ϯ2%. The hypotension induced by LNP 509 (100 g/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I 1 -imidazoline binding sites (I 1 BS). A synergy between LNP 509 and the ␣ 2 -adrenergic agonist ␣-methylnoradrenaline (␣-MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ventricle injection) but not, as expected, in D79N mice. Similar to LNP 509 alone, rilmenidine (fourth ventricle injection), which binds both to ␣ 2 -adrenergic receptors and to I 1 BS, decreased BP in D79N mice. In WT animals, rilmenidine had a significantly greater effect. Microinjections performed in rabbits showed that the synergism occurred at least in part in the nucleus reticularis lateralis of the brain stem. Conclusions-These results demonstrate that a central imidazoline-sensitive, but non-␣ 2 -adrenergic, mechanism can modify BP by itself. This mechanism, which may involve I 1 BS, interacts synergistically with an ␣ 2 -adrenergic mechanism to decrease BP.

The I 1 subtype of imidazoline receptors (I 1 R) is a plasma membrane protein that is involved in diverse physiological functions. Available radioligands used so far to characterize the I 1 R were able to bind with similar affinities to ␣ 2 -adrenergic receptors (␣ 2 -ARs) and to I 1 R. This feature was a major drawback for an adequate characterization of this receptor subtype. New imidazoline analogs were therefore synthesized and the present study describes one of these compounds, 2-(2-chloro-4-iodophenylamino)-5-methyl-pyrroline (LNP 911), which was of high affinity and selectivity for the I 1 R. LNP 911 was radioiodinated and its binding properties characterized in different membrane preparations. Saturation experiments with [

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The 2 -receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of 2 receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac 2 receptors in the regulation of cardiac K ϩ channel conductances and ii) to check whether 2 -receptor agonists exhibit class III antiarrhythmic properties. , and 1,3-di(2-tolyl)guanidine were used to discriminate the effects linked to 2 receptors from those of the 1 subtype, induced by (Ϯ)-N-allylnormetazocine (SKF-10,047). The 2 -receptor antagonist 3-␣-tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize 2 -mediated effects in patchclamp experiments. In rabbits, all 2 -receptor agonists reduced phenylephrine-induced cardiac arrhythmias. They prolonged action potential duration in rabbit Purkinje fibers and reduced human ether-a-go-go-related gene (HERG) K ϩ currents. (ϩ)-SKF-10,047 was completely inactive in the last two tests. The effects of threoifenprodil were not antagonized by SM-21. In HERG-transfected COS-7 cells, SM-21 potentiated the ifenprodil-induced blockade of the HERG current. These data suggest that 2 -receptor ligands block I Kr and that this effect could explain part of the antiarrhythmic properties of this ligands family. Nevertheless, an interaction with HERG channels not involving 2 receptors seems to share this pharmacological property. This work shows for the first time that particular caution has to be taken toward ligands with affinity for 2 receptors. The repolarization prolongation and the earlyafterdepolarization can be responsible for "torsades de pointe" and sudden cardiac death.